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Genomic characterization of <i>SMARCA4</i> -mutant versus wild-type non–small cell lung cancer in a Chinese population: A large-scale next-generation sequencing study.

8547 Background: SMARCA4 is a core component of the SWI/SNF chromatin remodeling complex and plays a critical role in transcriptional regulation and tumor suppression. SMARCA4 mutations define a biologically aggressive subset of lung cancer; however, their genomic landscape and clinical implications in Chinese patients with non–small cell lung cancer (NSCLC) remain incompletely characterized. This study aimed to comprehensively compare the genomic alteration profiles between SMARCA4-mutant and SMARCA4–wild-type NSCLC to better define distinct molecular subtypes and potential therapeutic implications. Methods: A total of 2,362 Chinese patients with NSCLC underwent comprehensive next-generation sequencing (NGS) using a 733-gene DNA panel. The prevalence and mutation spectrum of SMARCA4 were analyzed. Genomic alteration profiles, including co-occurring mutations, tumor mutational burden (TMB), and microsatellite instability (MSI) status, were systematically compared between SMARCA4-mutant and wild-type tumors. Results: SMARCA4 mutations were identified in 29 of 2,362 patients (1.23%). The mutation spectrum included frameshift (10.34%), nonframeshift (10.34%), nonsynonymous missense (51.72%), stop-gain (24.14%), and synonymous (3.45%) alterations. SMARCA4-mutant tumors exhibited a distinct genomic profile compared with wild-type tumors. Several genes were significantly enriched in the SMARCA4-mutant group, including STK11 (25.0% vs 5.8%, P &lt; 0.001), FAM135B (25.0% vs 8.2%, P = 0.0068), CDH10 (17.9% vs 4.2%, P = 0.0063), and FUBP1 (7.1% vs 0.3%, P = 0.0036), suggesting increased genomic instability and aggressive tumor biology associated with chromatin remodeling dysfunction. In contrast, EGFR mutations were significantly enriched in the SMARCA4–wild-type group (49.1% vs 14.3%, P &lt; 0.001), indicating a strong mutual exclusivity between SMARCA4 alterations and classical EGFR-driven oncogenesis. SMARCA4-mutant tumors also demonstrated a significantly higher tumor mutational burden compared with wild-type tumors (7.8 vs 3.1 muts/Mb, P &lt; 0.0001), whereas no significant difference in MSI status was observed between the two groups. Conclusions: SMARCA4-mutant NSCLC represents a distinct molecular subtype characterized by enrichment of tumor suppressor gene alterations, chromatin remodeling dysfunction, and elevated TMB, while SMARCA4–wild-type tumors are predominantly driven by canonical tyrosine kinase oncogenes such as EGFR. These findings highlight fundamental differences in tumor biology and suggest divergent therapeutic strategies, with SMARCA4-mutant NSCLC potentially benefiting from immunotherapy-oriented approaches rather than traditional targeted therapies.

Analysis of information received and perceived by patients with metastatic breast cancer: Results of the Croyances et Réalités 3 French survey.

1113 Background: Despite therapeutic advances, metastatic breast cancer (mBC) and its treatments substantially impact quality of life. This impact, as well as prognosis and treatment strategies, varies by histological subtype. The Croyances et Réalités 3 (R3) survey, building on the 2015 and 2020 editions (R1 and R2), provides a longitudinal perspective on how French mBC patients perceive information and the support they receive. Methods: R3 was a multicenter, cross-sectional mirror survey involving patients with recurrent or de novo mBC (HR+/HER2−, HER2+, Triple-negative (TN)), and oncologists who completed paired questionnaires. Subgroup analyses were prespecified by histological subtype. Results: The survey was completed by 331 patients with mBC and 56 oncologists, enabling robust patient–physician comparisons with 80% mirroring. Mean patient age was 64 and 37% lived alone. Only 10% were still in the workforce while 58% were retired. The mean medical consultation duration was 40 minutes and in 26% of cases, was followed by a consultation with a nurse. Patients showed good understanding of their histological subtype, with 62% able to report it correctly (vs 37% in R2). Communication metrics also improved: 86% of patients felt their physician took time to explain, 79% felt listened to, and 69% reported good comprehension, closely matching physicians’ perceptions (&gt;80%). For 28% of patients, the treatment decision was shared, while 35% would like to be more involved. Supportive care and disease information brochures were the most common resources handed out (60% and 47% respectively). Uptake of supportive care increased to 65% overall (53% in R2). Psychologist (48% vs 36% in R2), dietitian (44% vs 26%), oncology aesthetician (35% vs 26%), and adapted physical activity (28% vs 18%) use increased. Among patients who did not seek supportive care, 37% stated that it was not offered to them, while 38% stated that they did not wish to receive it. Regarding impact of the disease on daily life, patients with HER2+ and TN mBC reported greater physical burden, including general fatigue and pain with significant impact (HER2+: 52%, TN: 50% vs HR+/HER2−: 33%), and reported greater use of supportive care (HER2+: 67%+, TN: 72% vs HR+/HER2−: 49%). The use of patient associations remained limited, at 11%. Conclusions: This current study R3 documents meaningful progress—patients’ knowledge of their disease has improved, and oncologists have enhanced communication and supportive care delivery. However, despite recent improvements, supportive care remains underutilized, while the burden of the disease and its treatments remain substantial, underscoring the need to formalize care pathways that systematically integrate supportive care. Further progress is needed to improve shared decision-making, a recognized patient priority.

Immune checkpoint inhibitor (ICI) toxicity in a large prospective cohort of patients with solid tumors: The I-CHECKIT study (SWOG S2013).

2640 Background: Based on clinical trials, the expected rate of ≥ grade 3 iRAEs is ~15% for single agent ICIs and ~30-50% for ipilumimab (ipi) plus nivolumab (nivo). Predictors of irAEs remain poorly defined, limiting clinicians’ ability to anticipate and manage irAEs especially in patients treated in community practices. We conducted a prospective study to quantify the incidence and severity of irAEs across a large, diverse population of patients receiving ICI therapy and to identify clinical predictors of irAE development. Methods: S2013 enrolled adult patients planning to receive standard of care ICI-based therapy in two separate cohorts; only results from the completed first cohort, which received either single drug or combination (combo) ICI therapy, are reported here. Eligibility criteria were few and study included patients with active autoimmune disease, decreased performance status, and any stage of cancer. No chemo, biological or targeted therapy were permitted. Patients were followed for 1 year for the occurrence of irAE. The primary objective was to assess the occurrence of Grade &gt;3 non-hematologic irAEs per CTCAE v5. Evaluable patients had 1 or more toxicity assessment. irAE events were centrally reviewed by the study team. Results: 2084 patients were enrolled and N=2,020 patients were eligible (96.9%). Mean (SD) age was 68.7 (12.5) years, 35.8% were female, 5.2% Black, and 8.0% Hispanic. Most patients received single drug (1,684; 83.4%), while 336 (16.6%) received combo. Majority of single drug patients received pembrolizumab (50.6%), followed by nivo (29.6%), durvalumab (14.0%), and ipi (13.8%). Combinations were mostly ipi plus nivo. Within the first year, 269 (13.3%) patients experienced Grade ≥3 non-hematologic irAE. The most common irAEs were hepatitis, 21.2%; gastrointestinal disorders, 19.3%; and respiratory, 10.0% (Table). IrAE incidence was higher in patients receiving combinations (27.4%) compared to single drug (10.5%; Chi-square p&lt;.001). Conclusions: In this large prospective cohort with unrestrictive enrollment criteria, irAE incidence was similar to that seen in more restrictive clinical trial populations. Analysis of the clinical predictors of irAEs is in progress. Grant: NIH/NCI UG1CA189974. Clinical trial information: NCT04871542 . Grade ≥3 non-hematologic irAEs, by category. irAE n % irAE n % Hepatitis 57 21.2 Metabolism/nutrition 19 7.1 Gastrointestinal 52 19.3 Musculoskeletal 12 4.5 Skin 32 11.9 Cardiac 9 3.3 Respiratory 27 10.0 Hepatobiliary 7 2.6 Endocrine 22 8.2 Nervous system 7 2.6

A novel peptide decoy DMp39 targeting mitochondrial metabolism to enhance chemotherapy response.

e20720 Background: Chemotherapy resistance remains a major clinical challenge, leading to treatment failure and disease relapse. Although protein acetylation is known to regulate cancer cell survival, the role of mitochondrial acetylation signaling in chemotherapy resistance is poorly understood. Here, we found the novel non-canonical function of mitochondrial dihydrolipoyl transacetylase (DLAT) in regulating chemotherapy response. Methods: An acetylome-focused RNA interference screen was performed to identify acetylation-related regulators of cisplatin resistance. Mechanistic studies included interaction proteomics, mutational analyses, metabolic profiling, and mitochondrial functional assays. Clinical relevance was assessed using tumor specimens from patients treated with chemotherapy or chemoimmunotherapy. The therapeutic potential of a decoy peptide (DMp39) targeting DLAT-MTHFD2 was evaluated in cell line- and patient-derived xenograft (PDX) mouse models. Results: DLAT was identified as a key driver of chemotherapy resistance across multiple cancer types. DLAT directly acetylated methylenetetrahydrofolate dehydrogenase 2 (MTHFD2) at lysine 44, activating tetrahydrofolate metabolism by increasing 10-formyl-tetrahydrofolate levels. This metabolic rewiring induces expression of mitochondrial-encoded cytochrome c oxidase II (MT-CO2), reduces chemotherapy-induced mitochondrial reactive oxygen species, and promotes cancer cell survival during chemotherapy. Elevated DLAT signaling, including MTHFD2 acetylation, was observed in tumors from patients refractory to chemotherapy or chemoimmunotherapy. A decoy peptide, DMp39, which competes with MTHFD2 for acetylation by DLAT, was designed. DMp39 restored chemotherapy sensitivity and significantly suppressed tumor growth in PDX models without overt toxicity. Conclusions: Our study identifies a DLAT-MTHFD2 acetylation axis that mediates mitochondrial metabolic reprogramming as a critical mediator of chemotherapy resistance. Targeting this pathway with the unique decoy peptide DMp39 represents a promising therapeutic strategy to overcome resistance and enhance chemotherapy outcomes.

Real-world outcomes of enfortumab vedotin plus pembrolizumab compared with platinum-based chemotherapy in metastatic urothelial carcinoma in a propensity-matched global analysis.

e16597 Background: Enfortumab vedotin plus pembrolizumab has shown superior efficacy compared with platinum-based chemotherapy in randomized trials for untreated locally advanced or metastatic urothelial carcinoma. However, comparative real-world evidence evaluating survival and healthcare utilization with enfortumab vedotin plus pembrolizumab versus platinum-based chemotherapy remains limited. This study examines real-world outcomes associated with these treatment strategies in routine clinical practice. Methods: We conducted a retrospective cohort study using the TriNetX Global Collaborative Network. Adult patients ( &gt; 18 years) with metastatic urothelial carcinoma initiating first-line enfortumab vedotin plus pembrolizumab or platinum-based chemotherapy (gemcitabine with cisplatin or carboplatin) between January 2020 and December 2024 were identified. One-to-one propensity score matching (PSM) was performed to balance baseline demographics and key clinical comorbidities, including chronic kidney disease, diabetes, neuropathy, and smoking history. The primary outcome was overall survival (OS). Secondary outcomes included inpatient hospitalization and palliative care encounters. Kaplan–Meier analyses, log-rank testing, and hazard ratios (HRs) were calculated. Risk differences and risk ratios were estimated for secondary outcomes. All outcomes were assessed in the matched cohorts. Results: Among 2,264 eligible patients, 851 received enfortumab vedotin plus pembrolizumab and 1,413 received platinum-based chemotherapy. After PSM, 771 patients were included in each group with well-balanced baseline characteristics. Median OS was significantly longer in the enfortumab vedotin plus pembrolizumab group compared with platinum chemotherapy (679 vs 467 days), corresponding to a 20% reduction in mortality risk (HR 0.80; 95% CI 0.70–0.92; p = 0.002). Patients treated with enfortumab vedotin plus pembrolizumab also experienced fewer inpatient hospitalizations (62.5% vs 71.9%) and fewer palliative care encounters (39.9% vs 46.3%) compared with those receiving platinum-based chemotherapy. Median follow-up duration was similar between groups (392 vs 453 days). Conclusions: In this large real-world propensity-matched analysis, first-line enfortumab vedotin plus pembrolizumab was associated with improved overall survival and lower healthcare utilization compared with platinum-based chemotherapy in metastatic urothelial carcinoma. These findings support the effectiveness of enfortumab vedotin plus pembrolizumab in routine clinical practice and provide complementary evidence to randomized trials, particularly for patients who may be underrepresented in clinical trial populations.

Long-term real-world outcomes of axicabtagene ciloleucel (axi-cel) in relapsed/refractory (R/R) large B-cell lymphoma (LBCL).

7028 Background: Axi-cel, autologous anti-CD19 CAR T-cell therapy, showed long-term survival and curative potential in R/R LBCL (ZUMA-1; Neelapu et al. Blood . 2023). Few studies have examined long-term outcomes beyond clinical trials. Here we report long-term real-world outcomes of axi-cel in R/R LBCL using large-sample CIBMTR data. Methods: A total of 1500 adults from 79 US centers receiving commercial axi-cel after ≥2 LOT for LBCL from Oct 2017-Aug 2020 were enrolled in a post-marketing requirement study. A protocol was developed prior to the study’s implementation, reviewed by Kite and CIBMTR. This is a secondary analysis of said study. Key outcomes were progression-free survival (PFS), overall survival (OS), time to next therapy (TTNT), disease-specific mortality (competing risks were non-relapse deaths), subsequent malignancies, and non-relapse mortality (NRM). Outcomes were analyzed descriptively. Cases with missing data were excluded separately for each endpoint. Results: As of Aug 2025, 1446 patients (pts) were included in the analysis. Median age at infusion was 62.2 y (range, 19.6-90.8: 38% of pts ≥65 y); 65% were male. Five percent of pts had ECOG PS ≥2 and 16% had high-grade lymphoma. Pts had a median of 3 (range, 2-4) prior LOT, 28% had prior autologous hematopoietic cell transplantation, and 50% received bridging therapy. At 59.7 mo median follow-up, median PFS (95% CI) was 7.9 mo (6.3-10.9) and 5-y PFS was 30% (27-32). The median OS was 25.7 mo (21.6-30.2); 5-y OS was 38% (35-41). The 5-y cumulative incidence of disease-specific mortality was 51%. Among pts who were progression-free at 2, 3, 4, or 5 y post-infusion, the OS at 6 y (95% CI) was 73% (68-78), 81% (76-86), 90% (84-94), and 94% (89-97), respectively. The median duration of response (DOR) was 25.3 mo (95% CI, 20.7-32.8) and 5-y DOR was 38% (35-41). The median TTNT was 12.2 mo and 30% did not need additional LOT at 5 y. Of pts who received subsequent salvage therapy, 12 (2%) received cell therapy, 39 (7%) received hematopoietic cell transplant, and 475 (90%) received other therapy. The 1, 2, 3, 4, and 5-y cumulative incidence of relapse (95% CI) was 49% (46-51), 52% (50-55), 54% (52-57), 55% (53-58), and 56% (53-59), respectively. No new safety signals were observed. The primary causes of death (n=864; 60%) were primary disease (540; 63%), infection (111; 13%), and organ failure (57; 7%). The 5-y cumulative incidence of NRM was 16% (95% CI, 14-18). At 5 y, 11% (95% CI, 10-13) had subsequent malignancies, mostly therapy-related myeloid neoplasms (6%) and non-melanoma skin cancer (3%); none were directly attributed to axi-cel. Conclusions: This real-world study showed sustained survival at 5 y among pts with R/R LBCL treated with axi-cel after ≥2 LOT, consistent with ZUMA-1. Infection and organ failure were common causes of NRM. These results continue to support the use of axi-cel with curative intent in R/R LBCL.

Envafolimab (KN035) plus gemcitabine and oxaliplatin (GEMOX) compared with GEMOX as first-line treatment for Chinese patients with advanced biliary tract cancer: A randomized, open-label, multi-center, phase III pivotal trial.

4118 Background: China bears a high biliary tract cancer (BTC) burden, with cholangiocarcinoma rising incidence ( &gt; 6/100,000 vs 0.3–6/100,000 globally) and high mortality ( &gt; 4/100,000). Over 60% of BTC patients are diagnosed at advanced stage (stage III/IV), and nearly two-thirds are unresectable. GEMOX regimen is a widely recognized standard of care in China, favored for its reduced renal toxicity and better tolerability compared with GemCis. Envafolimab is the world's first subcutaneously (SC) injectable anti-PD-L1 monoclonal antibody approved by China's NMPA. We report the final analysis of this pivotal trial, the first global phase III study initiated to evaluate immunotherapy plus chemotherapy in this setting. Methods: In this multicenter, open-label, phase III study in China, eligible patients (pts) with previously untreated, unresectable locally advanced/metastatic BTC were randomized 1:1 to envafolimab (2.5 mg/kg SC weekly) + GEMOX (gemcitabine 1000 mg/m² d1, 8; oxaliplatin 85 mg/m² d1, Q3W) or GEMOX chemotherapy alone. Chemotherapy was limited to 6 cycles in both arms. Stratification factors: primary site, disease stage, prior therapy, and ECOG PS. Primary endpoint: OS. Secondary endpoints: PFS, ORR (RECIST v1.1 by BICR), and safety. Results: 472 pts were randomized; 462 treated (envafolimab+GEMOX n = 232; GEMOX n = 230). At the final analysis, the primary endpoint was met well. Envafolimab+GEMOX significantly improved OS vs GEMOX (HR 0.723; 95% CI 0.585–0.880; P = 0.0016). Median OS was 10.9 months vs 8.6 months; 36-mo OS rates were 12.5% vs 7.7%. OS benefit was observed across subgroups, notably in intrahepatic cholangiocarcinoma (HR 0.705) and metastatic disease (HR 0.704). Median PFS (BICR) was 4.8 vs 4.6 months (HR 0.899; 95% CI 0.713–1.132); notably, the gallbladder cancer subgroup showed more favorable PFS benefit (HR 0.628). ORR was 27.6% vs 20.9%. Grade 3–4 TEAEs occurred in 69.4% (combination) vs 56.1% (chemo). irAEs occurred in 20.7%. Conclusions: This study demonstrates that adding subcutaneously administered envafolimab to GEMOX significantly improves OS with a manageable safety profile in advanced BTC. Compared with other regimens, the combination showed robust efficacy with a low rate of irAEs. Those findings establish envafolimab, the world's first SC PD-L1 inhibitor, combined with GEMOX as a new, effective, and convenient standard of care for this population. Clinical trial information: NCT03478488 .

Novel isocryptolepine analogs with submicromolar antiproliferative activity: En route to next-in-class antiestrogens for the treatment of breast cancer.

e15166 Background: Estrogen receptor α (ERα)-positive breast cancer (BC) comprises ~70% of cases. Despite advances in endocrine therapy, a lot of patients develop resistance, necessitating novel therapeutic approaches. Indoloquinoline alkaloids, particularly isocryptolepines, represent a promising scaffold. We synthesized and evaluated novel isocryptolepine analogs with enhanced antitumor activity. Methods: Two series of derivatives (n = 27) were synthesized via photochemical cyclization of O -acetyl oximes. Antiproliferative properties and cytotoxicity were assessed by MTT assay (72 h) in BC cell lines MCF7, T47D (ERα+/PR+), HCC1954 (HER2+), and MDA-MB-231 (triple negative), and also in normal cell lines hFB-hTERT, MCF10A. The antiestrogenic activity of hit compound was evaluated using luciferase reporter assay with MCF7/ERE-Luc cells stimulated with 17β-estradiol (E2). The mechanism of action was investigated by western blotting and molecular docking to ERα. Results: Based on the IC 50 values, ranged from 0.24 to 11.4 μM on MCF7 cells, the most and least active indoloquinoline derivatives were isolated. Compound 6d with a fluorine atom at the R 3 position demonstrated pronounced selectivity toward ERα+ BC cells with IC 50 = 0.12 μM (T47D), SI &gt; 25. In luciferase reporter assay 125 nM 6d inhibited ERα transcriptional activity comparable to 4-hydroxytamoxifen (4-OHTam) at the concentration of 100 nM. Molecular docking revealed direct binding of 6d to ERα, with subsequent confirmation of its antiestrogenic activity through western blot analysis, which revealed significant decrease of ERα protein expression at 0.5 μM. Proapoptotic effects, including cleavage of PARP and downregulation of Bcl-2, were also found. Based on structure optimization, series 2 compound 7l, with methyl at R 5 , exhibited 7.4-enhanced antiproliferative potency in MCF7 (IC 50 = 42 nM) compared to hit 6d. Conclusions: We developed novel isocryptolepine analogs with potent ERα-antagonistic properties. Hit 6d demonstrates excellent cytotoxicity, pronounced selectivity for ERα+ BC cells, and dual mechanism of action. These findings warrant further preclinical evaluation of lead 7l, obtained after structure optimization of 6d, as a promising therapeutic candidate for treatment of ERα+ BC and its endocrine-resistant forms. Compound R 3 R 4 R 5 IC 50 values ± SD, μM MCF7 IC 50 values ± SD, μM MDA-MB-231 SI * (ERα– / ERα+) IC 50 values ± SD, μM MCF10A TI ** (norm / ERα+) 6a H H H 1.3 ± 0.1 0.70 ± 0.06 0.54 0.70 ± 0.07 0.54 6d F H H 0.31 ± 0.03 3.4 ± 0.5 11.0 2.3 ± 0.2 7.4 6h H CH 3 H 0.86 ± 0.09 0.68 ± 0.06 0.79 0.67 ± 0.7 0.78 6k F CH 3 H 0.26 ± 0.03 2.0 ± 0.1 7.7 1.5 ± 0.2 5.8 7c F Ac H 11.4 ± 1.1 &gt; 25 - 14.2 ± 1.5 1.2 7l F H CH 3 0.042 ± 0.003 2.4 ± 0.2 57.1 2.9 ± 0.3 69.0 tamoxifen - - - 6.41 ± 0.7 10.8 ± 1.2 1.7 15.6 ± 1.4 2.4 docetaxel - - - 0.0015 ± 0.0003 0.0059 ± 0.0004 3.9 0.0023 ± 0.0004 1.5 * SI – selectivity index, ** TI – therapeutic index.

Comprehensive molecular profiling in advanced non–small cell lung cancer (NSCLC): Measurable survival and value impacts of implementation.

11054 Background: Comprehensive molecular profiling (CMP) is key to precision oncology in advanced non–small cell lung cancer (NSCLC), enabling identification of actionable driver alterations and delivery of matched targeted therapies that improve survival. CMP has been universally recommended by international guidelines for over a decade. Despite mature evidence and widespread availability, real-world adoption remains strikingly low. We evaluated the real-world impact of molecular profiling on survival, healthcare utilization, and cost in NSCLC, and quantified the magnitude of its ongoing underuse. Methods: We analyzed NSCLC patients aged ≥18 years treated between January 2019 and December 2025 using two independent real-world datasets: TriNetX and Highmark Health. Patients were categorized based on receipt of broad-panel molecular profiling consistent with guideline-directed indications. Outcomes included overall survival (OS), emergency department (ED) visits, inpatient admissions, and healthcare costs. Survival was assessed using Kaplan–Meier methods, with multivariable regression to adjust for clinical factors. Results: Among 33,977 NSCLC patients in TriNetX, only 2,354 (6.9%) underwent molecular profiling, despite the majority of NSCLC patients presenting with advanced disease. Molecularly profiled patients experienced a substantial survival advantage, with median OS of 1,784 days versus 1,074 days in untested patients (adjusted hazard ratio 0.61; p&lt;0.001). Molecular profiling was also associated with significantly fewer inpatient admissions (0.651 vs 0.875; p&lt;0.001) and ED visits (0.437 vs 0.583; p=0.047). Highmark Health data independently validated these findings, demonstrating significantly improved 4-year OS in molecularly tested patients (55% vs 43%; p&lt;0.001). Importantly, these survival gains were achieved without a statistically significant increase in total cost per patient per month at follow-up (p=0.083). Conclusions: Across two large, independent real-world datasets, comprehensive molecular profiling in NSCLC was associated with meaningful improvements in survival and reductions in healthcare utilization, even when applied primarily in advanced disease. These benefits were achieved without a significant increase in overall costs, supporting the value-based impact of precision oncology. Yet fewer than 1 in 15 eligible NSCLC patients underwent molecular profiling between 2019 and 2025, revealing a profound and persistent failure to implement guideline-concordant care. This underuse directly translates into avoidable mortality and unnecessary healthcare utilization. System-level solutions, including standardized and reflexive molecular testing at diagnosis, are urgently needed to ensure precision medicine is delivered as standard care in advanced NSCLC patients.

Final results from a phase II study of tislelizumab combined with radiotherapy as bladder-preserving treatment for high-risk non–muscle-invasive bladder cancer patients unresponsive to Bacillus Calmette-Guerin.

4599 Background: Radical cystectomy (RC) was the standard of care for high-risk non-muscle-invasive bladder cancer (HR NMIBC) patients with Bacillus Calmette-Guerin (BCG)-unresponsive papillary tumors. Clinical unmet need was to explore non-surgical treatment options for patients who were ineligible for or declined RC. Our study was established to evaluate the efficacy and safety of tislelizumab combined with radiotherapy as bladder-preserving treatment for HR NMIBC patients unresponsive to BCG. Methods: This open-label, single arm phase II study enrolled HR NMIBC patients with BCG-unresponsive papillary tumors (high-grade Ta or T1 tumors without carcinoma in situ). The papillary tumors should be removed all visible lesions by transurethral resection of bladder tumor (TURBT). Within 2 weeks after TURBT, eligible patients received tislelizumab 200 mg in day 1 (D1), every 21 days for eight cycles and a total radiotherapy dose of 60-66 GY in 30-33 fractions over seven weeks. The primary endpoint was disease-free survival (DFS) rate at 12 months (defined as no reappearance of high grade or T1 tumors or clinical stage development after the therapy). Secondary endpoints were bladder-preservation rate, OS and safety. Our study estimated a DFS rate at 12 months was no less than 50% and the study would enroll 32 patients to meet the primary endpoint. Results: Between September 4, 2020, and December 11, 2024, 32 patients (26 [81.2%] men and 6 [19.8%] women) who had received a median of eleven (IQR 7-22) previous BCG instillations were enrolled. Patients received a median of 8 cycles (IQR 8–8) of tislelizumab and of radiotherapy doses of 62.0 GY (IQR 62.0–64.0) . Median follow-up was 28.8 months (19.7-43.8). The DFS rate at 12 months was 90.6% (95%CI, 79.8%-99.6%), at 24 months was 70.2% (95%CI, 50.1%-83.4%). The bladder-preservation rate at 24 months was 93.2% (95%CI, 75.4%-98.3%). The OS rate at 24 months was 100% (95%CI, 100%-100%). The OS rate at 36 months was 90.5% (95%CI, 67.0%-97.6%). Treatment-related adverse events (TRAEs) occurred in 27 (84.4%) of 32 patients, 7 (21.9%) patients had a grade 3 TRAEs. The most common 3 TRAEs were diarrhea (9.4%), radiocystitis (3.1%), leukopenia (3.1%) and liver function damage (3.1%) without grade 4-5 TRAEs. Conclusions: Our final results supported the use of tislelizumab combined with radiotherapy as a promising bladder-preserving therapy for BCG-unresponsive HR NMIBC patients who were ineligible for or decline RC. Clinical trial information: ChiCTR2000035275.

Impact of VT-EBV-N on disease-free survival as post-remission therapy in EBV-positive extranodal NK/T-cell lymphoma: A randomized, double-blind, placebo-controlled phase 2 study.

7005 Background: Extranodal NK/T-cell lymphoma (ENKL) is an aggressive EBV-associated malignancy. Although complete remission (CR) can be achieved with intensive therapy, patients with high-risk features remain at substantial risk of relapse, and no standard post-remission therapy exists. VT-EBV-N is an autologous EBV-specific cytotoxic T lymphocyte (EBV-CTL) therapy designed to eliminate residual EBV-infected malignant cells. This phase 2 study evaluated the efficacy and safety of VT-EBV-N as post-remission therapy in patients with EBV-positive ENKL. Methods: This randomized, double-blind, placebo-controlled phase 2 trial enrolled patients with EBV-positive ENKL who had achieved CR within 6 months prior to enrollment and had at least one predefined high-risk factor for relapse. Patients were randomly assigned (1:1) to receive VT-EBV-N or autologous peripheral blood mononuclear cells (PBMC) as control. Treatment was administered IV weekly for 4 weeks, followed by a 4-week rest, and then once weekly for an additional 4 weeks (total 8 doses). The primary endpoint was 2-year disease-free survival (DFS). Secondary endpoints included overall survival (OS) and safety. Efficacy was analyzed in the full analysis set (FAS), and safety was assessed in the safety set. Results: A total of 50 patients were randomized, and 46 patients (VT-EBV-N, n=21; control, n=25) were included in the FAS. Baseline characteristics and distributions of high-risk features were generally balanced between groups. At 2 years, VT-EBV-N demonstrated a clinically meaningful and significant improvement in DFS compared with control (95.0% vs 77.6%). DFS events occurred in 1/21 patients (4.8%) in the VT-EBV-N group and 8/25 patients (32.0%) in the control group. Stratified log-rank analysis confirmed a significant DFS benefit with VT-EBV-N (p=0.0347). No deaths occurred in the VT-EBV-N group, whereas 4 deaths (16.0%) were observed in the control group; the difference in OS did not reach statistical significance (p=0.0580). VT-EBV-N was generally well tolerated. Most adverse events (AEs) were grade 1–2. Grade ≥3 AEs (CTCAE) occurred in 2/21 patients (9.52%) in the VT-EBV-N group and 4/25 patients (16.00%) in the control group. No treatment-related deaths were reported. Conclusions: VT-EBV-N demonstrated a clinically meaningful improvement in disease-free survival with a favorable safety profile in patients with EBV-positive ENKL in complete remission and at high risk of relapse. These findings support VT-EBV-N as a promising post-remission therapeutic option for this rare and aggressive lymphoma. Clinical trial information: KCT0003592. Key efficacy and safety outcomes. Outcome VT-EBV-N Control (PBMC) Patients analyzed (FAS), n 21 25 2-year DFS, % 95.0 77.6 DFS events, n (%) 1 (4.8) 8 (32.0) Deaths, n (%) 0 (0.0) 4 (16.0) Grade ≥3 AEs, n (%) 2 (9.52) 4 (16.00)

Trends and racial disparities in pulmonary embolism–related mortality among older adults with neoplasms: A population-based retrospective study in the United States from 1999-2020.

11157 Background: Pulmonary embolism (PE) remains a major cause of preventable mortality, particularly among older adults with cancer who face heightened thrombotic risk. Understanding temporal trends in PE-related deaths is essential for guiding prevention and early detection. This study evaluates national patterns and racial disparities in PE-related mortality among older adults with neoplasms. Methods: We performed a retrospective cross-sectional analysis of the national death certificate data from the CDC's WONDER database. We included persons ≥65 years of age with neoplasms (ICD-10 code C00-D48) as the underlying cause of death and PE (ICD-10 code I26) as a contributing cause of death. The exposure variable was the year of death, and the outcome was PE-related age-adjusted mortality rate (AAMR) stratified by sex, race, rural-urban status, and census region. We calculated the PE-related AAMR in neoplasm per 100,000 population. Trends were evaluated with Joinpoint regression and expressed as an average annual percentage change (AAPC) with a 95% confidence interval (CI). P &lt; 0.05 defined statistical significance. Results: Of 928 million people, 104,743 PE-related deaths occurred in older adults with neoplasms (AAMR 11.4). The AAMR was higher in males (13.3 vs 10.1 in females; P &lt; 0.01), Black (17.0 vs 11.2 in White, P &lt; 0.000001), and the Midwest census region (12.3 vs 11.7 in NorthEast, the Midwest, and 10.4 in the South; P &lt; 0.0001). The AAMR was similar in rural areas (11.4 vs 11.3 in urban areas, P &lt; 0.000001). The overall PE-related AAMR in neoplasms increased from 8.7 to 14.1 (AAPC 4.03%; CI: 3.12- 5.23). Furthermore, the AAMR increased in males (AAPC 3.37%; CI: 1.61-6.6) and females (AAPC 4.53%; CI: 3.15-6.20). Similarly, it increased in Black (AAPC 3.14%; CI:2.42-4.07), White (AAPC 3.98%; CI:3.07-5.14), rural (AAPC 3.70%; CI: 2.69-5.39), urban (AAPC 4.24; CI: 3.44-5.23 ), and across all geographic census regions. Conclusions: Pulmonary embolism related mortality among older adults with neoplasms has risen steadily over the past two decades across all demographic and geographic groups. Given that cancer-associated thrombosis is a well-recognized and largely preventable complication, these findings suggest important gaps in the prevention, recognition, and management of PE in oncology populations at the health-system level. The consistent upward trend highlights an urgent need to strengthen thromboprophylaxis strategies, risk stratification, and early detection efforts in older adults with cancer to reduce avoidable mortality.

Expression of Concern: Genetic diversity and population structure of pigeonpea (Cajanus cajan [L.] Millspaugh) landraces grown in Benin revealed by Genotyping-By-Sequencing

Nanomedicine in photodynamic therapy: A comprehensive strategy for improved outcomes in lung cancer

Soft Ionic and Electronic Triboelectric Nanogenerators: Toward Attachable and Implantable Biomedical Applications (Adv. Mater. 32/2026)

Backbone Engineering of Carbon‐Centered NHC‐Derived Diradicals: From Electronic State Tuning to High‐Performance Organic Field‐Effect Transistors

ABSTRACT Diradicals have gained interest for their unique electronic properties and potential applications in organic electronics and semiconductors. However, precise manipulation of electronic states and achieving satisfactory device performance remain challenging. Herein, we report the synthesis and characterization of tetraphenylethylene‐bridged salts and their neutral diradical counterparts obtained via two‐electron reduction. With extended conjugation and electron‐withdrawing N‐heterocyclic carbene (NHC) backbones, enhanced open‐shell character is observed. Through this systematic study, a backbone engineering strategy is established that allows precise control over spin states and diradical character in carbon‐centered NHC diradicals. Leveraging this strategy, compound 2d , with moderate diradical character induced by extended conjugated structures and strong electron‐withdrawing groups, was employed in a spin‐coated organic field‐effect transistor (OFET) device. The device achieved a record‐high hole mobility of 4.53 cm 2 ·V −1 ·s −1 , representing exceptional performance among open‐shell organic semiconductors for high‐performance OFETs. This not only demonstrates the outstanding charge‐transport capability of 2d but also underscores the significant potential of this approach for developing functional open‐shell organic semiconductors.

Multi-objective optimization of an energy-efficient diaphragm spring for clutch applications

C-terminal dimerization motifs control asynchronous chain elongation during modular polyketide biosynthesis

Cabozantinib in high-grade neuroendocrine neoplasms.

4183 Background: High grade neuroendocrine neoplasms (HG-NENs) are treated with platinum doublets mirroring guidelines for small cell lung cancer (SCLC) but recurrences are common and salvage options are limited in efficacy. Cabozantinib (CABO), an inhibitor of VEGFR, MET, and TAM kinases (TYRO3, AXL, and MER) was approved by the FDA for treatment of well differentiated (WD) NENs of both pancreatic and extrapancreatic origins based on the CABINET study (Chan, NEJM 2025). However, its efficacy in the whole spectrum of HG-NEN patients including poorly differentiated disease (PDD) has not been prospectively explored. Methods: This was a single institution, Phase II study of CABO in patients with HG-NENs who had progressed on at least one prior treatment. Key inclusion/exclusion criteria were NENs of any origin except SCLC, high grade by Ki-67 of &gt; 20% or histology consensus, ECOG of &lt; = 1, appropriate hematological parameters and no history of bleeding or active cardiac disease. CABO was given orally starting at 60 mg po daily in 3-week cycles. The primary endpoint of this study was overall response rate (ORR). Secondary endpoints included progression free survival (PFS) and overall survival (OS). A Simon optimal 2-stage design tested the null hypothesis that the true ORR is &lt; = 1% at the type I error rate of 5%, resulting in projected enrollment of up to 32 total patients. Toxicities were graded according to CTCAE v5.0 and response was evaluated according to RECIST v1. Results: All patients have been accrued, with 4/32 patients still on treatment. Median age at diagnosis was 62 years and male to female ratio was 1.46. Origin of tumor was GI in 68.8% of the cases, the rest being thoracic (6.3%), prostate (6.3%) cervical (6.3%) head/neck (3.1%) and unknown (9.4%). Median Ki-67 was 55%, 11 patients had Ki-67 &gt; 70%. Histology was WD-HG in 40% of patients and PDD in 60%. Two patients had mixed PDD/other components (MiNEN). Median PFS in evaluable patients was 4.01 months [95% CI 1.61 to 9.30] and mOS was 9.89 mo [95% CI 6.73 to 18.96]. Three patients so far (9.3%) have had partial response as best response (PDD-colon, WD-pancreas and PDD-cervical) while 19/32 (59.4%) patients have had stable disease as best response so far (disease control rate 68.8%). Five (15.6%) patients have received more than 10 treatment cycles. The three longest treated patients had WD-pancreas (23 and 17 cycles) and PDD-unknown (12 cycles). One patient had eventual resection of a metastatic site and is currently without evidence of disease. Three patients withdrew from the trial because of toxicities (shortness of breath, GI bleeding, thromboembolism). Twenty-six patients have expired. Conclusions: CABO monotherapy showed efficacy in some HG-NEN patients with not just WD but also the very aggressive PDD histology. No new side effects to the ones previously described for this agent were noted. Supported by Exelixis and a Siteman investment program grant. Clinical trial information: NCT04412629 .

Patient trust in oncologists versus artificial intelligence for cancer-related questions.

11105 Background: Artificial intelligence tools, including the recent introduction of ChatGPT Health, are increasingly accessible to patients seeking medical information. In oncology, where discussions surrounding prognosis and treatment are highly sensitive, trust in the source of information is critical. However, patient perspectives on AI tools compared with oncologists for cancer-related questions remain poorly characterized. Methods: We conducted a cross-sectional survey of 75 adult cancer patients at an academic safety-net oncology clinic. The survey assessed patients’ perspectives on technology use and their trust in AI tools like ChatGPT compared with oncologists for cancer-related questions. The primary outcome was patients’ preferred source of trust when asked who they would rely on most to answer a serious question about their cancer. Secondary outcomes assessed attitudes toward physician versus AI trust using Likert-scale items and comfort engaging with AI for cancer-related questions. Binomial proportions are reported with 95% confidence intervals. Spearman correlation and Fisher’s exact tests were used for secondary exploratory analyses. Results: Among 75 respondents, the median age group was 55–64 years; 42.7% were male and 57.3% female. English was the primary language for 53.4% and Spanish for 43.8%. The most common cancer types were gastrointestinal (24.0%), breast (20.0%), and hematologic malignancies (17.3%). For the primary outcome, when asked who they would trust most to answer a serious question about their cancer's future, an overwhelming majority selected their oncologist (97.3%; 73/75; 95% CI 90.7–99.7). No respondents selected ChatGPT/AI (0%; 95% CI 0–4.8), while 2.7% were unsure (95% CI 0.3–9.3). In secondary analyses, greater self-reported comfort with technology was associated with greater comfort engaging with AI tools for cancer-related questions (Spearman ρ = 0.40, p &lt; 0.001). In exploratory subgroup analyses, Spanish speakers showed a trend toward less agreement that they would trust a doctor’s answer more than AI (71.9% vs 87.2%). This may reflect increased trust when medical information is delivered in a patient’s primary language. In addition, a similar directional signal was observed among younger patients (73.3% vs 84.4%). Conclusions: Cancer patients currently demonstrate a strong preference for oncologists over AI tools when addressing serious cancer-related questions, underscoring the central role of physician trust in oncology care. However, comfort engaging with AI varies by technological familiarity, suggesting that this preference may evolve over time as younger, more digitally fluent generations enter care and AI becomes increasingly integrated into healthcare. This study highlights the potential of AI tools to support oncologists in providing more accurate and individualized prognostic estimates for patients with advanced malignancies.