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A phase 1, first-in-human study of OP-3136, a novel oral selective KAT6A/B inhibitor, as monotherapy in advanced solid tumors and in combination with endocrine therapy in ER+, HER2− advanced breast cancer (ABC): Preliminary results.

3088 Background: Histone lysine acetyltransferases (KATs) control oncogenic transcription and are frequently dysregulated in cancer. OP-3136 is a potent, selective, oral small-molecule inhibitor of KAT6A/B with preclinical antitumor activity, including in combination with endocrine therapy (ET) (Palanisamy et al, 2024). This phase 1 study evaluates the safety, tolerability, pharmacokinetics (PK), and preliminary antitumor activity of OP-3136 as monotherapy in advanced solid tumors and in combination with fulvestrant or palazestrant (a novel oral complete estrogen receptor antagonist [CERAN] and selective estrogen receptor degrader [SERD]) in ER+, HER2− ABC (NCT06784193). Methods: Patients (pts) with ABC, metastatic castration-resistant prostate cancer (mCRPC), or non-small cell lung cancer (mNSCLC) received OP-3136 once daily (QD) as monotherapy (no limit on prior lines of therapy), and a separate cohort of ABC pts received OP-3136 + fulvestrant in a phase 1 study using a Bayesian Optimal Interval dose-escalation. Results: As of 26 November 2025, 32 pts ABC, n=23; mCRPC, n=8; and mNSCLC, n=1) received OP-3136 (monotherapy, n=25; in combination with fulvestrant, n=7) across doses of 2–45 mg QD. All ABC pts received prior endocrine therapy and CDK4/6 inhibitors, all mCRPC pts received prior androgen receptor–targeted therapy. The median (min – max) of prior anticancer systemic therapy lines was 3 for ABC (1–5) and 5 (1–8) for mCRPC pts. The median time on treatment was approximately 2 months (max 47 months). In the monotherapy cohort, treatment-related adverse events (TRAEs) were mostly grade (G)1–2. The most common (≥25%) TRAEs included dysgeusia (72%; G2, 24%), anemia (40%; G3, 8%), fatigue (32%; G2, 16%), and neutropenia (28%; G3, 20%). In the combination cohort, TRAEs were predominantly G1–2 with one G3 neutropenia and leukopenia. No dose-limiting toxicities (DLTs), G4-5 TRAEs or treatment discontinuations due to TRAEs were reported. Across monotherapy dose levels, among 14 pts with measurable disease, reduction of target lesions occurred in 64% (9/14) and 2 pts (1 with ABC and 1 with mCRPC) had partial responses (unconfirmed). Among 17 pts with evaluable disease,10 had stable disease. PK analyses showed dose-proportional exposure of OP-3136 with rapid absorption and sustained systemic exposure over the dosing interval supporting QD administration. Conclusions: OP-3136 demonstrated a manageable safety profile and favorable PK, both as monotherapy and in combination with fulvestrant. Preliminary evidence of antitumor activity in ER+ HER2- ABC and mCRPC was observed in these heavily pretreated pts. Dose escalation and enrollment in combination with fulvestrant or palazestrant are ongoing and updated data will be presented. Clinical trial information: NCT06784193 .

Intratumoral heterogeneity of <i>MTAP</i> loss by immunohistochemistry in non–small cell lung cancer: Implications for clinical outcomes.

8025 Background: MTAP-cooperative PRMT5 inhibitors are under development for MTAP-loss solid tumors including non-small cell lung cancer (NSCLC). However, the intratumoral heterogeneity of MTAP loss in NSCLC and its potential implications for clinical outcomes remain incompletely understood. Methods: Tumor specimens from patients with NSCLC who underwent surgical resection between January 2019 and October 2019 in our institution were retrospectively collected. MTAP expression status was evaluated in surgically resected specimens using MTAP immunohistochemistry (IHC) 2G5 and categorized as retained (100% positive tumor cells), partial loss (1–99%), or complete loss (0%). MTAP status was confirmed by fluorescence in situ hybridization (FISH). Clinicopathological characteristics and survival outcomes were analyzed according to MTAP expression status. Results: MTAP expression status was successfully analyzed in 196 specimens from primary lesion of patients with NSCLC. MTAP expression status was classified as retained in 131 specimens (67%), partial loss in 43 (22%), and complete loss in 22 (11%). Of 14 specimens of which MTAP status was evaluated by FISH, the MTAP status by IHC and FISH were completely consistent. Compared to the patients with retained, the patients with complete loss showed no significant differences in the clinicopathological characteristics, but the patients with partial loss were significantly more frequently associated with adenocarcinoma histology (93% vs 74%, P = 0.02) and never-smoker status (51% vs 22%, P &lt; 0.001). Among specimens diagnosed as adenocarcinoma, those with partial loss showed a significantly higher frequency of lepidic and papillary predominant patterns compared to those with complete loss (83% vs 50%, P = 0.02). Among specimens of which EGFR mutation status was analyzed, the frequency of EGFR mutations was significantly higher in specimens with MTAP complete/partial loss compared to MTAP retained (59% vs 30%, P = 0.03). There were no significant differences in the recurrence-free survival (RFS) and the overall survival (OS) among the patients with complete loss, partial loss and retained (5-year RFS rates: 82%, 83% vs 76%, 5-year OS rates: 90%, 81% vs 77%). MTAP expression status of corresponding metastatic lymph node (mLN) was evaluated in 6 patients with MTAP partial loss. MTAP expression status for corresponding mLN were consistent with predominant MTAP expression status for primary lesion in 4 patients (67%). Conclusions: Intratumoral heterogeneity of MTAP expression was observed in 22% of NSCLC, particularly with adenocarcinoma histology and in never-smokers. Intratumoral heterogeneity of MTAP loss may contribute to inaccurate assessment of MTAP status on small biopsy samples. MTAP expression status was not associated with the prognosis in patients with surgically resected NSCLC.

Performance of a cfDNA methylation–based MCED test in patients with clinicoradiologic suspicion of cancer.

10543 Background: Radiographic findings concerning for malignancy frequently prompt extensive diagnostic evaluations that fail to yield a definitive diagnosis, resulting in delayed treatment, persistent uncertainty, and unnecessary interventions. Multi-cancer early detection (MCED) tests based on circulating cell-free DNA (cfDNA) methylation have demonstrated high specificity in asymptomatic screening populations; however, performance in individuals with clinical suspicion of malignancy remains unclear. We compared the performance of a cfDNA methylation–based MCED test in asymptomatic participants and in participants with imaging-based suspicion of malignancy. Methods: Adults aged 45–79 years enrolled in CORE-HH (NCT05435066) were evaluated in (1) a case–control cohort (n = 4,137) comprising asymptomatic participants who reported no history of cancer (n = 2,523) and newly diagnosed cancer participants (n = 1,614); and (2) a prospective cohort (n = 209) of individuals with imaging-based suspicion of malignancy undergoing clinical evaluation (cancer confirmed, n = 155; no cancer, n = 54). Cancer types included lung, breast, colorectal, prostate, pancreatic/hepatobiliary, head and neck, gynecologic, and hematologic malignancies. Samples were analyzed using a cfDNA methylation–based MCED test incorporating an AI/ML model, at a pre-specified specificity of 98.5%. Test performance was compared between cohorts among non-cancer participants and among early-stage (stage I–II) and late-stage (stage III–IV) cancer cases using Fisher’s exact test (two-sided). Results: Among non-cancer participants (n = 2,577), empirical specificity was 98.1% (53/54) in the clinical suspicion cohort and 98.5% (2,485/2,523) in the asymptomatic case–control cohort (OR, 1.23; 95% CI, 0.03–7.6; p = 0.56). Overall sensitivity was 54.8% (85/155) in the clinical suspicion cohort and 53.9% (870/1,614) in newly diagnosed cancer cases from the case–control cohort (OR, 1.04; 95% CI, 0.74–1.47; p = 0.87). Stage I–II sensitivity was 27.7% (18/65) vs 28.7% (204/711) (p = 1.00), and stage III–IV sensitivity was 82.9% (58/70) vs 81.5% (573/703) (p = 0.87), for the clinical suspicion and case–control cohorts, respectively. Overall cancer stage distribution was similar between cohorts (p = 0.89). Conclusions: At the prespecified 98.5% specificity threshold, the cfDNA methylation–based MCED test demonstrated comparable specificity and sensitivity in prospectively enrolled participants undergoing evaluation for imaging-based suspicion of malignancy and in a case–control cohort of newly diagnosed cancer cases versus asymptomatic controls. Recognizing the tendency of case–control designs to overestimate test performance, these results describe MCED test performance in a cohort with clinical suspicion of malignancy, extending characterization beyond asymptomatic screening populations. Clinical trial information: NCT05435066 .

Overcoming HER2-directed antibody-drug conjugate resistance with disitamab vedotin in metastatic prostate cancer.

e17078 Background: Metastatic prostate cancer (PCa) is a highly aggressive disease with limited treatment options following castration resistance. Prior studies have associated elevated Human Epidermal Growth Factor Receptor 2 (HER2) protein expression with advanced stage PCa, prompting evaluation of HER2 as a therapeutic target using HER2-directed antibody-drug conjugates (ADCs). Furthermore, clinical co-expression of HER2 with Epidermal Growth Factor Receptor (EGFR) or Human Epidermal Growth Factor Receptor 3 (HER3) has been implicated in other solid tumors for HER2 ADC resistance due to receptor heterodimerization and impaired ADC internalization. Therefore, we aimed to investigate HER2 ADC resistance using metastatic PCa models with elevated HER2 and variable EGFR and HER3 expression to support rational development of HER2-targeted therapy such as Disitamab Vedotin (DV) into clinical trials. Methods: We identified metastatic castration-resistant PCa cell line and organoid model systems representative of HER2 ADC resistance using RNAseq gene expression datasets from Human Protein Atlas and the Gene Expression Omnibus platform (GSE199596). HER2, EGFR, and HER3 protein expression was confirmed by immunofluorescence. The efficacy of HER2 ADCs was evaluated in cell lines and PDXOs using 2D and 3D CellTiter-Glo, respectively, complemented by image-based analysis. ADC internalization was assessed using pH-sensitive dye–labeled HER2 ADCs and live-cell imaging with Incucyte. Results: HER2 ADCs were screened in two metastatic PCa cell lines, DU145 and LNCaP clone FGC. Despite distinct receptor expression profiles, with DU145 characterized by high EGFR and LNCaP clone FGC by high HER3 expression, DV retained cytotoxic efficacy across both models. Patient-derived xenograft organoids (PDXOs) from the LuCaP PDX series were evaluated for gene expression of the targets with LuCaP 167 emerging as a suitable model confirming increased HER2, EGFR, and HER3 expression and membrane localization. Notably, DV induced robust cytotoxicity and significant organoid disintegration in LuCaP 167 PDXOs. Incucyte analysis further confirmed efficient ADC internalization in both cell lines and PDXOs, demonstrating that EGFR and HER3 expression did not prevent DV internalization. Conclusions: These findings demonstrate that DV retains efficacy across metastatic prostate cancer models independent of EGFR and HER3 expression and may overcome EGFR and HER3-associated resistance mechanisms reported with other HER2 ADCs. Our study also supports the further translational development of HER2-targeted ADCs for patients with metastatic prostate cancer.

Neoadjuvant and adjuvant enfortumab vedotin plus pembrolizumab for participants with muscle-invasive bladder cancer who are eligible for cisplatin: Randomized, open-label, phase 3 KEYNOTE-B15 study.

4614 Background: Enfortumab vedotin (EV) + pembrolizumab (pembro) is the established first-line standard of care for locally advanced/metastatic urothelial carcinoma and represents a novel neoadjuvant and adjuvant treatment strategy for patients with muscle-invasive bladder cancer (MIBC) who are ineligible for cisplatin-based chemotherapy. The randomized phase 3 KEYNOTE-B15/EV-304 study (NCT04700124) evaluates neoadjuvant EV + pembro followed by radical cystectomy plus pelvic lymph node dissection (RC + PLND) and adjuvant EV + pembro vs neoadjuvant chemotherapy followed by RC + PLND in participants (pts) with MIBC who are eligible for cisplatin-based therapy. Methods: Pts with clinical stage T2-T4aN0M0 or T1-T4aN1M0 MIBC (confirmed by central pathology and central imaging assessment) who were eligible for cisplatin-based chemotherapy and RC + PLND were randomized 1:1 to receive either 4 cycles neoadjuvant EV 1.25 mg/kg IV on days 1 and 8 + pembro 200 mg IV on day 1 Q3W, followed by RC + PLND, and adjuvant 5 cycles EV + 13 cycles pembro (EV + pembro arm) vs 4 cycles neoadjuvant gemcitabine 1000 mg/m 2 on days 1 and 8 + cisplatin 70 mg/m 2 on day 1 Q3W, followed by RC + PLND (cis + gem arm). The primary endpoint was event-free survival (EFS) by blinded independent central review. Key secondary endpoints were pathological complete response (pCR) rate by blinded central pathological review and overall survival (OS). Safety was a secondary endpoint; AEs of special interest were based on distinct prespecified lists for each drug. Results: A total of 405 and 403 pts were randomized to EV + pembro and cis + gem, respectively. Median time from randomization to the data cutoff date of October 27, 2025 was 33.6 months (range, 22.5–53.6). Baseline characteristics were generally balanced between groups. EV + pembro significantly improved EFS (median NR vs 48.5 mo; 24-mo estimated EFS rate 79.4% vs 66.2%; HR 0.53, 95% CI 0.41–0.70; 1-sided P &lt;.0001), OS (median NR vs NR; 24-mo estimated OS rate 86.9% vs 81.3%; HR 0.65, 95% CI 0.48–0.89; 1-sided P =.0029), and pCR rate (55.8% vs 32.5%; estimated difference 23.4%, 95% CI 16.7–29.8; 1-sided P &lt;.0001) vs cis + gem. Grade ≥3 treatment-emergent AEs occurred in 75.7% of pts with EV + pembro and 67.2% with cis + gem. Most common grade ≥3 drug-related AE of special interest for EV was skin reactions (14.1%); most common grade ≥3 AE of special interest for pembro was severe skin reactions (13.9%). Conclusions: Neoadjuvant and adjuvant EV + pembro significantly improved EFS, OS, and pCR rate compared with neoadjuvant gem + cis in pts with MIBC who were eligible for cisplatin-based chemotherapy. The safety profile of EV + pembro was consistent with prior experience with the combination. These results support EV + pembro as an effective perioperative treatment option in this setting. Clinical trial information: NCT04700124 .

Comparative analysis of large language models (LLMs) for pharmacogenomic (PGx)–guided prescribing in oncology.

e13665 Background: PGx is increasingly applied in oncology to personalize drug therapy, minimize toxicity, and improve efficacy. LLMs have shown potential in providing medical recommendations, though their performance in PGx is not well understood. This study evaluates LLMs’ performance in providing chemotherapy prescribing recommendations based on PGx results using a modified version of the previously developed Generative AI Performance scoring (G-PS) tool. Methods: Six single-gene and four multi-gene oncology PGx theoretical cases were developed for gene-drug pairs with established prescribing guidance: DPYD-fluoropyrimidines, UGT1A1-irinotecan, and TPMT/NUDT15-thiopurines. Prompts followed the structure: “ My patient is a [gene] [phenotype] with a genotype of [genotype]. How does this result affect [drug] prescribin g?” . LLMs tested included ChatGPT 5.2, Copilot (Think Deeper), Gemini (Google AI Overview), and OpenEvidence. Each case was queried three times per LLM on a private browser, except OpenEvidence, which was queried once due to login requirement. Each response was evaluated for accuracy per guidelines (FDA, CPIC, or NCCN) and weighted across up to three domains: drug selection, dose selection, and dose modification. Penalty was applied per the number and severity of hallucinations. A modified G-PS (mG-PS) grading scheme generated a final score for each LLM response, ranging from -1 (all hallucinations) to 1 (fully correct). Grading was performed by oncology and PGx pharmacists and a pharmacy student. Results: Table 1 reports mean mG-PS and percentage of responses with at least one hallucination or missing information across all LLMs. Across 10 cases, OpenEvidence had the highest mean mG-PS (0.88) and the lowest rate of hallucination (10%). Among LLMs tested in triplicate, ChatGPT had the highest mean mG-PS (0.82), followed by Copilot (0.68), and Gemini (0.54). ChatGPT and Copilot had the highest rates of hallucination (48%), followed by Gemini (35%). Gemini most frequently provided inadequate or no recommendations (60%). Conclusions: Performance across LLMs was variable. OpenEvidence showed the highest accuracy with the fewest hallucinations, though its use remains limited to healthcare professionals. Among publicly available LLMs, ChatGPT performed comparatively well but still produced high rates of hallucinations and incomplete information. Clinicians should be cautious when using LLMs in clinical practice, and in the case of PGx, continue to rely on guidelines such as CPIC. The modified G-PS tool offers a structured framework for assessing LLM performance in PGx and can be applied to more complex multi-gene PGx cases in oncology and supportive care. ChatGPT Copilot Gemini OpenEvidence Mean mG-PS 0.82 0.68 0.54 0.88 Any Hallucinations 48% 48% 35% 10% Major Hallucinations 7% 13% 10% 10% Minor Hallucinations 42% 37% 25% 0% Missing Information 37% 45% 60% 30%

Outcomes with adjuvant chemotherapy in patients with early-stage biliary tract cancers: An NCDB analysis.

e16302 Background: Biliary tract cancers (BTCs) are a heterogeneous group of malignancies, collectively associated with poor prognosis. Treatment typically consists of curative intent surgery for eligible candidates. Based on the landmark BILCAP trial, capecitabine is currently used as an adjuvant therapy for pts with BTCs. However, the trial included a small number of pts with early-stage disease. Additionally, the staging system used for the trial was updated since. Methods: This retrospective review was based on the National Cancer Data Base (NCDB) participant user file (PUF) from 2014 to 2023. Patients (pts) were identified using codes for intrahepatic biliary, extrahepatic biliary, or gallbladder adenocarcinoma who underwent curative intent surgical resection and had documented chemotherapy status. Only node-negative (N0) disease, pathological stage T1 or 2 were included. Pts were categorized by receipt of adjuvant chemotherapy versus no chemotherapy. Overall survival was evaluated using Kaplan–Meier survival analysis. Analysis of the NCDB PUF is exempt from IRB review. Results: A total of 11,111 pts were identified. 79.3% were White; 44.3% were male; mean age was 67.9years. 2,975 (26.8%) had intrahepatic cholangiocarcinoma (CCA), 2,687 (24.5%) extrahepatic CCA, and 5,449 (49.0%) had gallbladder adenocarcinoma. 9,237 (85.5%) had negative margins; 6,093 (75.7%) had negative LVI. As for size, 3,525 (38.2%) had tumors 2cm or less, 3,953 (42.8%) had tumors between 2 and 5cm, and 1,760 (19.0%) had tumors larger than 5cm. 6,932 pts (62.4%) received adjuvant chemotherapy. A trend toward improved survival was observed across most groups. Statistical significance was associated for T1a and T2a with negative LVI; T1a, T2a, and T2b with negative margins; and T1a and T1b intrahepatic CCA, T2a and b extrahepatic CCA, T2a and b gallbladder adenocarcinoma. The remaining groups had low numbers of pts, and the survival analyses were either not performed due to low numbers or were not statistically significant. Conclusions: Despite the limited retrospective nature of this analysis, adjuvant chemotherapy appears to be associated with improved survival in pts with early-stage CCAs, including those with favorable tumor features. Pt and tumor specific features should be considered individually.

Machine learning–based decision support for ICU admission in febrile oncology patients: Optimizing care delivery and resource allocation.

1598 Background: In febrile oncology patients, distinguishing self-limiting illness from life-threatening sepsis is a critical challenge for care delivery, particularly in resource-constrained settings. Over-triage strains limited critical care capacity, while under-triage compromises patient safety. We aimed to develop and validate a machine learning–based decision support tool to assist clinical judgment in identifying patients requiring intensive care. Methods: In a retrospective cohort of 149 febrile oncology patients, we extracted routinely available clinical features (including MASCC score, qSOFA, hypotension status, tumor characteristics, and comorbidities). We developed an XGBoost classifier to predict ICU admission and compared its performance against logistic regression and standard clinical risk scores (MASCC, qSOFA). Model performance was rigorously evaluated using 10×5-fold cross-validation with bootstrap confidence intervals, with specific attention to its utility as a supportive screening tool. Results: Of 149 patients, 81 (54.4%) required ICU admission. The XGBoost model demonstrated superior discrimination with an AUROC of 0.934 (95% CI: 0.863-1.000), significantly outperforming logistic regression (0.917), MASCC (0.656), and qSOFA (0.838). The model showed excellent calibration (Brier score: 0.092). Crucially, in a sensitivity analysis excluding hypotension—a clinically obvious trigger for ICU transfer—the model retained high discriminative ability (AUROC 0.887), indicating its value in identifying high-risk patients before hemodynamic collapse. Conclusions: This machine learning model effectively identifies febrile oncology patients requiring ICU admission, significantly outperforming traditional scores. By functioning as a high-fidelity decision support tool, it holds the potential to improve care delivery outcomes: ensuring timely escalation for high-risk patients while preventing unnecessary resource utilization for stable patients. Ultimately, this tool is designed to augment, rather than supersede, expert clinical judgment in complex acute care settings.

Center-level delivery patterns and capacity during rapid CAR-T expansion in the United States (2021-2023).

11089 Background: Chimeric antigen receptor T-cell (CAR-T) therapy has rapidly expanded in the United States, accompanied by substantial growth in utilization and expenditures. However, whether this expansion has been matched by proportional growth in delivery capacity and how CAR-T workload is distributed across centers remains unclear. Methods: We conducted a national retrospective analysis using publicly available Medicare administrative data from 2021-2023 obtained from the Medicare Inpatient Hospitals dataset on data.cms.gov. CAR-T hospitalizations were identified using the diagnosis-related group (DRG) descriptions for CAR-T therapy and other immunotherapies. Active CAR-T centers were defined annually based on inpatient discharges. This DRG-based approach may include non-CAR-T immunotherapies, and Medicare data captures primarily older adults, potentially missing younger patients with acute lymphoblastic leukemia and lymphoma. Center-level CAR-T volume and expenditures were aggregated annually. Per-center delivery burden was assessed by strain (total CAR-T discharges divided by number of active centers). Concentration of CAR-T delivery across centers was evaluated using cumulative contribution analyses. Results: From 2021 to 2023, active CAR-T centers increased from 23 to 46, while total CAR-T discharges rose from 544 to 1,303. Total annual CAR-T expenditure increased substantially over the same period, from $728 million in 2021 to $2.56 billion in 2023. Despite this expansion, median annual discharges per center remained relatively stable (24 in 2021 vs 25.5 in 2023), while mean discharges increased from 23.7 to 28.3, indicating that growth was driven disproportionately by higher-volume centers. Correspondingly, the center-level strain increased from 23.6 to 28.3, reflecting rising per-center delivery burden. CAR-T delivery remained moderately concentrated across years, with top quartile of centers (approximately 21.7% of centers) accounting for 37.3% of CAR-T discharges in 2021, increasing to 39.5% of discharges in 2023. Conclusions: Despite rapid expansion in CAR-T centers and substantial growth in utilization and expenditures, delivery is increasingly concentrated among higher-volume centers. Stable median per-center volumes alongside increasing mean volumes and persistent concentration patterns suggest that growth has outpaced effective distribution of delivery capacity. While the relationship between center volume and patient outcomes remains incompletely characterized, these findings highlight the need for workforce development, infrastructure investment, and policy strategies to support both high-volume centers experiencing rising delivery burden and lower-volume centers developing expertise, ensuring sustainable and equitable CAR-T delivery as utilization continues to expand.

Tuning Selectivity in Reductive Amination Through Orbital Symmetry Engineering of Metal‐Organic Supports

ABSTRACT Controlling selectivity in the reductive amination of carbonyls, a pivotal green route to amines, remains a long‐standing challenge within complex reaction networks. Here, we report a strategy to precisely steer product selectivity by engineering the orbital symmetry of coordinatively unsaturated metal sites (CUSs) on metal‐organic layers (MOLs) that support ruthenium nanoparticles (Ru NPs). Across diverse substrates, Zn‐based MOLs with Zn 2 (CO 2 ) 4 paddle‐wheel secondary building units (SBUs) favor primary amines, whereas their Cu‐based analogues with Cu 2 (CO 2 ) 4 SBUs solely produce Schiff bases. This divergence originates from a picoscale symmetry‐broken Cu‐O 4 geometry in the Cu 2 (CO 2 ) 4 unit, which weakens the adsorption and activation of Schiff base intermediates, thereby kinetically retarding their further ammonolysis. Our work establishes a paradigm for controlling catalytic selectivity through picoscale orbital symmetry manipulation at support metal sites.

Wearable technologies in clinical trials for drug development: trends and emerging opportunities

Increased Endurance of Nonvolatile Photonics Enabled by Nanostructured Phase‐Change Materials

ABSTRACT The rapid rise of artificial intelligence, and in‐memory computing has reinvigorated research on scalable, energy‐efficient, and reconfigurable photonic hardware. Non‐volatile phase‐change materials (PCMs) are attractive, as they offer large refractive index contrast, wavelength‐scale footprints, and zero static power consumption. However, current PCM‐based electrically controlled photonic devices are plagued by high insertion loss and low endurance. One prevalent hypothesis for these material limitations come from electromagnetic scattering in the interface and large programming volumes, respectively. Here, we validate this hypothesis by showing that nano‐structuring of PCM minimizes optical loss and enhances the endurance. By tapering both ends of a wide bandgap PCM Sb 2 Se 3 segment on a silicon waveguide, we suppressed the insertion loss by ≈94% (resulting in a loss of ≈0.1 dB per π phase shift). Through combining tapering and segmentation, we achieved high optical modulation amplitude (≈70%), low loss (≈0.5 dB per π phase shift), low‐voltage (&lt;5 V) actuation, and record high endurance greater than 100 million cycles. This work showcases the substantial advantage of nanopatterning PCMs to attain low loss and high cyclability.

Induction CAPOX as part of total neoadjuvant therapy for high-risk locally advanced rectal cancer: Long-term real-world outcomes from two centers.

e15650 Background: Recent randomised trials support total neoadjuvant therapy (TNT) for high-risk locally advanced rectal cancer (LARC); however, the optimal chemotherapy regimen and sequencing strategy remain uncertain. Induction chemotherapy administered prior to chemoradiotherapy (CRT) may improve systemic disease control, treatment compliance, dose intensification and tumour response. We report long-term outcomes from two centres using induction capecitabine-oxaliplatin (CAPOX) prior to CRT. Methods: Consecutive patients with MRI-defined high-risk non-metastatic LARC and threatened circumferential resection margin (CRM) treated at two oncology centres (first Oncology appointment Centre1:2004–2016; Centre2:2015–2018) were retrospectively reviewed via an agreed protocol. Patients were intended to receive four cycles of induction CAPOX followed by long-course CRT and total mesorectal excision or watch-and-wait if radiology and biopsy proven complete response. Patients were included irrespective of surgical approach. Progression-free survival (PFS) and overall survival (OS) were estimated using Kaplan-Meier methods. Cox regression evaluated prognostic factors. Results: One hundred thirty-six patients were included (Centre1 n = 75; Centre2 n = 61), including ten patients with T4 disease considered potentially unresectable at baseline. Median follow-up was 72 and 104 months, respectively. Chemotherapy completion was 89% and CRT completion 98.5%. Five-year PFS and OS were 59.2% and 68.2% in Centre1 and 78% and 83% in Centre2. This likely reflects higher baseline risk at Centre1, with more T4 (38.7% vs 24%) and node-positive disease (94.7% vs 87%). Pathological complete response or sustained clinical complete response (watch-and-wait) occurred in 12% and 33%, respectively. Tumour and nodal downstaging occurred in 46.7% and 70.7%. On univariate analysis, R1 resection (HR9.9,95%CI1.12–87.5,p &lt; 0.0001) and extramural venous invasion (HR4.59,95%CI1.5–14.04,p = 0.0006) were associated with inferior PFS. Conversion from node-positive to node-negative status was associated with improved PFS (HR3.25,95%CI1.36–7.76,p = 0.0014). On multivariable analysis adjusting for age, post-treatment nodal positivity remained independently associated with inferior PFS (HR6.02,95%CI1.09–33.39,p = 0.04). Conclusions: In this real-world cohort with long-term follow-up, induction CAPOX as part of TNT was associated with survival and response outcomes comparable to contemporary TNT studies. Post-treatment nodal response appears to be a dominant prognostic biomarker and may inform future risk-adapted sequencing, escalation and de-escalation strategies. This approach may be particularly relevant for patients unsuitable for intensive triplet chemotherapy regimens.

A phase I, open-label, dose-finding, safety, tolerability, and exploratory trial of intraperitoneal THEO-260 in patients with high-grade serous or endometrioid ovarian cancer.

TPS5635 Background: Ovarian cancers are immunologically cold at baseline and typically characterized by a rich stromal component with a high proportion of cancer-associated fibroblasts (CAF). These features limit efficacy of immunotherapy and virotherapy due to the immunosuppressive effects of abundant CAFs. THEO-260 is an oncolytic adenovirus that exhibits selective replication, lysis, and killing of cancer cells and CAFs. This unique mechanism-of-action positions THEO-260 as a potential efficacious treatment option for patients with platinum-resistant ovarian cancer. Intraperitoneal (IP) delivery may further enhance efficacy by enabling high locoregional dose with lower systemic exposure. Methods: This phase I, open-label, single-institution study (NCT07211659) evaluates IP THEO-260 in patients with platinum-resistant or refractory high grade serous (HGS) or endometrioid ovarian, peritoneal, or fallopian tube cancer. The primary objectives are to evaluate the safety and tolerability of THEO-260 when administered intraperitoneally and to establish the recommended phase 2 dose (RP2D) using a Bayesian Optimal Interval design with 4 dose levels in cohorts of 3. Patients receive up to 6 doses of THEO-260 over 15 days: 2 desensitization doses followed by 4 target-dose administrations. Secondary objectives include PK, viral shedding, systemic cytokine release, and preliminary efficacy assessment. Response assessments will be conducted every 8 weeks starting on day 29 through week 52 and thereafter every 12 weeks until progression, death, or end of trial. Eligibility includes histologically confirmed, platinum-resistant or refractory HGS, endometrioid cancer of the ovary, peritoneum, or fallopian tube, measurable peritoneal disease per RECIST v1.1, ECOG 0-1, adequate organ function, life expectancy of ≥6 months, and feasibility of intraperitoneal catheter placement. Prior treatments must include optimal surgical debulking, bevacizumab, or PARP inhibitor therapy as indicated. Key exclusions include serosal disease &gt;3cm, bowel obstruction history or symptoms, uncontrolled pleural or pericardial effusions, and prior pneumonitis or interstitial lung disease. Enrollment began in November 2025. Clinical trial information: NCT07211659 .

RETRACTED: Neoadjuvant adebrelimab plus chemotherapy in untreated locally advanced head and neck squamous cell carcinoma: Efficacy and biomarker insights from a single-arm phase 2 trial.

6106 Background: Improving outcomes for locally advanced head and neck squamous cell carcinoma (LA-HNSCC) requires novel strategies. This phase 2 trial evaluated the efficacy and safety of neoadjuvant adebrelimab (a PD-L1 inhibitor) combined with chemotherapy in untreated, resectable LA-HNSCC. Methods: In this single-center, single-arm study, eligible patients had newly diagnosed, resectable stage III-IVA/B LA-HNSCC. Patients received three cycles of neoadjuvant adebrelimab (1200 mg), nab-paclitaxel (260 mg/m²), and carboplatin (AUC 5) every 21 days. The primary endpoint was objective response rate (ORR, RECIST v1.1). Secondary endpoints included safety, pathologic response, larynx preservation, and biomarker analysis. Results: Twenty-four patients were enrolled (median age 61.5 years; 91.7% male; 70.8% hypopharynx primary). Twenty-three completed all three cycles of neoadjuvant therapy and were evaluated. The ORR was 87.5% (21/24) in the intention-to-treat population and 91.3% (21/23) in the per-protocol population, including 5 complete and 16 partial responses. The larynx preservation rate was 95.8%. Pathologic complete response was observed in 3 of 7 surgical patients (42.9%). Significant downstaging occurred in T-stage (66.7%), N-stage (70.8%), and overall stage (54.2%). All patients with p16-positive tumors (8/8) and those with PD-L1 combined positive score ≥20 (8/8) achieved an objective response. Grade 3 adverse events occurred in 41.7% of patients (primarily hematologic toxicities), with no grade 4/5 events. Conclusion: Neoadjuvant adebrelimab plus chemotherapy demonstrated high response rates, promising organ preservation, and manageable toxicity in resectable LA-HNSCC. Biomarker analysis suggests p16 positivity and high PD-L1 expression may correlate with better response. Clinical trial information: ChiCTR2400091171 . Efficacy outcomes based on full analysis set (FAS). Efficacy Parameter Overall (N=24) Larynx (n=4) Hypopharynx (n=17) Oropharynx (n=3) Best Overall Response, n (%) CR 5 (20.8) 1 (25.0) 4 (23.5) 0 (0.0) PR 16 (66.7) 3 (75.0) 10 (58.8) 3 (100.0) SD 3 (12.5) 0 (0.0) 3 (17.6) 0 (0.0) PD 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) ORR 21 (87.5, ) 4 (100.0) 14 (82.4) 3 (100.0) (95% CI) (67.6 - 97.3) (39.8 - 100.0) (56.6 - 96.2) (29.2 - 100.0) (95% CI) (48.9 - 87.4) (19.4 - 99.4) (38.3 - 85.8) (29.2 - 100.0) Larynx Preservation Rate 23 (95.8) 4 (100.0) 16 (94.1) 3 (100.0) (95% CI) (78.9 - 99.9) (39.8 - 100.0) (71.3 - 99.9) (29.2 - 100.0) DCR 24 (100.0) 4 (100.0) 17 (100.0) 3 (100.0) (95% CI) (85.8 - 100.0) (39.8 - 100.0) (80.5 - 100.0) (29.2 - 100.0) Data are n (%, 95% CI). FAS: full analysis set (all enrolled patients receiving at least one treatment cycle); ORR: objective response rate (CR + PR); DCR: disease control rate (CR + PR + SD). Antitumor response was assessed according to RECIST v1.1.

Role of routine prognostic blood tests in evaluating chances of safely prolonged survival across all ages.

e16348 Background: Prognostic blood tests (PBTs) are independent predictors of survival and often outperform traditional clinical prognostic characteristics (CPCs). Low-dose chemotherapy may safely prolong survival in patients with a performance status of 0-2. Methods: Consecutive patients with advanced stage IV pancreatic cancer and performance status 0–2, either treatment-naïve or previously treated with 2 (1-3) standard multi-drug regimens, were administered one-third standard doses of gemcitabine and FOLFIRINOX. Upon progression, docetaxel and mitomycin C were added. Survival was evaluated using Kaplan–Meier and Cox regression analyses. Predefined cut points included age (&gt; 70, &gt; 65 years) and baseline PBTs, summarized by the A.L.A.N. score (0–2 favorable vs ≥3 unfavorable), incorporating serum albumin ( &lt; 3.5 g/dL), neutrophil-to-lymphocyte ratio (&gt; 3), lymphocyte-to-monocyte ratio ( &lt; 2.1), and absolute neutrophil count ( &gt; 8). Ideal cut points (ICP) were also assessed. All patients provided written informed consent, with IRB approval, FDA, and ClinicalTrials.gov registration. Results: Across all ages, favorable PBT subgroups comprised 70–85% of patients, including 53 treatment-naïve and 53 previously treated individuals. Median survival times ranged from 12 to 20 months, with 2-year survival rates of 20–38%, and no hospitalizations, treatment-limiting toxicities, or withdrawals. Median survival for patients aged &lt; 70 versus ≥70 years, 40 patients, was 12.5 versus 12.8 months, with 2-year survival of 21.4% versus 27.5% (p = 0.36). For patients aged &lt; 65 versus ≥65 years, 66 patients, median survival was 12.1 versus 12.6 months, with 2-year survival of 16% versus 30% (p = 0.056). PBTs demonstrated strong prognostic significance: A.L.A.N. score (p &lt; 10⁻⁹), serum albumin (p &lt; 10⁻⁷), absolute neutrophil count (p &lt; 10⁻⁶), neutrophil-to-lymphocyte ratio (p &lt; 10⁻³), and lymphocyte-to-monocyte ratio (p = 0.04). Ideal cut points further strengthened associations. No interaction was observed between age and individual PBTs (p = 0.44). Conclusions: Independent of age (55–80 years), or unfavorable PBTs, A.L.A.N. scores of 0–2 identify a substantial subset of patients, including a potentially doubling proportion of elderly individuals, with actionable survival exceeding 12 months and excellent safety using economical low-dose chemotherapy. Systematic archiving and use of PBTs may expand opportunities for geriatric oncology research, including treatment safety, substantially sparing hospitalizations, low-dose strategies, recombination and rechallenge approaches, enhanced geriatric evaluation tools, and targeted investigation of immune-mediated or host-cell resistance mechanisms. Clinical trial information: 119005 .

Patterns of cause of death among patients with subsequent primary malignancies after cutaneous melanoma: A SEER-based analysis (2000–2022).

e21605 Background: As survival after cutaneous melanoma improves, subsequent primary malignancies (SPMs) and non-cancer comorbidities increasingly influence long-term outcomes. We evaluated causes of death (COD) and clinicodemographic characteristics among decedents with melanoma and multiple primaries. Methods: We conducted a retrospective, population-based analysis using Surveillance, Epidemiology, and End Results (SEER) data from 2000–2022. The cohort included decedents with cutaneous melanoma and two or more primary malignancies in whom melanoma preceded a subsequent primary cancer (N = 29,942). Cause of death was obtained from SEER cause-specific classifications and examined in relation to clinicodemographic and treatment characteristics. Variables included sex, age at diagnosis, race/ethnicity, primary site (ICD-O-3/WHO 2008), SEER Summary Stage 2004, and treatment indicators (chemotherapy, radiation, surgery, regional lymph node surgery). Descriptive statistics and frequency distributions were generated, with graphical displays used to visualize cause-of-death patterns and temporal trends. Results: The cohort was predominantly male (71.6%) and non-Hispanic White (96.4%); mean age at diagnosis was 74.4 years (median 76; range 16–90). By sequence number, most patients had ≥2 primaries (2nd primary: 73.3%; 3rd: 17.8%; 4th: 4.9%). The most common indexed primary site category was melanoma of the skin (40.2%), followed by lung and bronchus (9.9%) and prostate (7.2%). Summary stage at diagnosis was localized in 33.9%, distant in 22.0%, in situ in 16.6%, and unknown/unstaged in 8.1%. Chemotherapy was recorded in 17.8%, while radiation was uncommon overall (none/unknown 84.2%; beam 13.1%). COD was most frequently melanoma (17.0%), followed by diseases of heart (13.1%), lung and bronchus cancer (9.7%), and “other cause of death” (9.1%). Additional notable COD categories included pancreas (3.6%), cerebrovascular disease (3.0%), and non-Hodgkin lymphoma (2.0%). Conclusions: In patients with melanoma and multiple primaries, melanoma remains a leading COD, but cardiovascular mortality represents a substantial competing risk. These findings support integrated survivorship strategies emphasizing both second-cancer surveillance and aggressive cardiovascular risk assessment and management.

A phase 1/2 dose-escalation/expansion study of REGN10597 (anti–PD-1–IL2Rα-IL2) in patients with advanced solid tumors.

TPS2675 Background: Interleukin 2 (IL-2) is a cytokine involved in lymphocyte expansion and differentiation during the anticancer immune response. Aldesleukin, an approved recombinant high-dose IL-2 therapy, has shown complete and durable responses in some cases; however, high-dose IL-2 is associated with severe toxicity, including vascular leak syndrome and pulmonary edema. Despite clinical advances with checkpoint inhibitor therapies, many advanced solid tumors continue to respond poorly to these treatments. REGN10597 is an antibody–cytokine fusion protein comprising a human anti–programmed cell death-1 antibody fused with a receptor-masked cytokine, IL2Rα-IL2. REGN10597 has demonstrated tumor inhibition, enhanced specificity, and reduced toxicity versus recombinant high-dose IL-2 in preclinical mouse models (Wu et al. Cell Rep Med 2024;5:101747). Here we describe BrILliance (NCT06413680), a study evaluating the safety, tolerability, pharmacokinetics, and preliminary antitumor activity of REGN10597 in patients with advanced solid tumors. Methods: This is an open-label, Phase 1/2, dose escalation/expansion, first-in-human, multicenter study evaluating REGN10597 in advanced or metastatic solid tumors. Patients must be aged ≥18 years with histologically or cytologically confirmed locally advanced or metastatic tumors and confirmed disease progression on standard-of-care therapy. During the dose escalation phase, patients will be enrolled to receive REGN10597 by intravenous infusion at the assigned dose level and schedule (additional dose schedules are available for further exploration). When the recommended Phase 2 dose level and schedule are determined, additional patients will be enrolled across two dose expansion cohorts: patients with locally advanced or metastatic melanoma (Cohort 1) and those with advanced or metastatic clear cell renal cell carcinoma (Cohort 2). Dose escalation primary endpoints include incidence of dose-limiting toxicities, incidence of treatment-emergent adverse events (including those leading to treatment discontinuation or death), incidence of serious adverse events, and the number of patients with Grade ≥3 laboratory abnormalities. The dose expansion primary endpoint is objective response rate per Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1) by investigator assessment. Secondary endpoints for both phases include additional efficacy measures (best overall response, duration of response, disease control rate, time to response, and progression-free survival, all per RECIST 1.1), and pharmacokinetics and immunogenicity of REGN10597. Trial enrollment for the dose escalation phase began on October 1, 2024; as of January 27, 2026, 22 patients have been enrolled. Clinical trial information: NCT06413680 .

Real-world survival analysis of adolescent and young adult patients with hairy cell leukemia in the United States.

e19031 Background: Hairy cell leukemia (HCL) is a rare indolent B-cell malignancy with favorable outcomes. Adolescents and young adults (AYA; ages 15–39) are underrepresented in population-based studies, and factors influencing outcomes in this group remain poorly defined. We evaluated survival and associated predictors among AYA patients with HCL in the United States using the National Cancer Database (NCDB). Methods: In this IRB approved retrospective analysis, AYA patients diagnosed with HCL between 2004–2023 were identified from the NCDB. Survival was estimated using Kaplan–Meier methods. Cox proportional hazards regression was used to evaluate predictors of mortality. Multivariable models included demographic characteristics, insurance status, Charlson–Deyo comorbidity score, treatment variables, and year of diagnosis. Subgroup analyses were performed among patients diagnosed from 2013–2023, reflecting the era in which rituximab was coded as immunotherapy. Results: Among 906 AYA patients identified, 850 had available vital status. A total of 37 deaths (4.4%) were observed, corresponding to approximately 96% survival at last follow-up. The cohort was predominantly male (77.3%) and White (91.5%), with most patients having Charlson–Deyo score 0. Higher comorbidity burden was associated with worse survival but the survival did not differ by receipt of systemic therapy versus no treatment recorded, or by time from diagnosis to treatment initiation (≤60 vs &gt;60 days). In multivariable analysis, insurance status was the strongest independent predictor of mortality; uninsured (HR 5.99, 95% CI 2.63–13.65; p&lt;0.001) and governmental insured patients (HR 3.03, 95% CI 1.37–6.73; p=0.006) had higher mortality compared with privately insured patients. Diagnosis during 2004–2013 was independently associated with lower mortality compared with 2013–2023 (HR 0.34, 95% CI 0.15–0.74; p=0.0066). In the 2013–2023 subgroup (n=471; 25 deaths), insurance status remained the only independent predictor of mortality. Immunotherapy was not associated with survival differences. Multi-agent chemotherapy was associated with worse survival compared with single-agent therapy in unadjusted analyses. Conclusions: AYA patients with HCL in the United States experience excellent population-level survival, with a low observed frequency of multiple primary malignancies. Despite this favorable prognosis, comorbidity burden and significant insurance-based disparities remain clinically relevant, underscoring the importance of equitable access to care and long-term follow-up. Baseline characteristics of AYA patients with HCL. Characteristic n (%) Male sex 657 (77.3) White race 764 (91.5) Charlson–Deyo score ≥1 50 (5.9) Private insurance 632 (76.1) Government insurance 130 (15.6) Uninsured 69 (8.3) Time to systemic therapy ≤60 days 657 (89.3) Any treatment received 538 (92.3)

Impact of population-based testing for pathogenic variants in breast cancer genes on screening recommendations in the WISDOM study.

10512 Background: The relative contributions of pathogenic variants (PV) in breast cancer (BC) genes, polygenic risk scores (PRS), and clinical risk factors to inform risk-stratified screening have not been well-studied on the population level. The WISDOM Study, a study of risk-based screening, used panel-based testing for PVs in 9 BC genes and the Breast Cancer Surveillance Consortium risk model modified by PRS (BCSC-PRS) to generate screening recommendations for &gt; 30,000 participants undergoing risk-based screening. Women with PVs in high-penetrance genes were assigned q6 month screening (alternating MRI and mammogram). Those with PVs in moderate-penetrance genes were assigned q6 screening or yearly mammogram depending on family history. To determine the impact of PV detection on screening assignments, we examined the concordance between screening strategies informed by PV status vs. BCSC-PRS only. Methods: We analyzed participants with high-penetrance ( BRCA1, BRCA2, TP53, PALB2, STK11, CDH1 ), moderate-penetrance ( CHEK2, ATM ), or CHEK2 low-penetrance (I157T, S428T) PVs. We performed cross-tabulations of hypothetical (based on BCSC-PRS only) vs. actual (which considers PV) screening recommendation. To generate hypothetical screening recommendations, we calculated individual BCSC-PRS 5-year risk and applied the trial’s risk-based screening algorithm as if there were no PV. We considered initial (Year 1) screening recommendations to reflect that PV testing occurred at time of enrollment. We stratified analyses by PV category and age. Results: Our analysis included 714 women with a PV, of which 32% were high-penetrance, 39% were moderate-penetrance, and 29% were CHEK2 low-penetrance. Median age was 53 (IQR 45-62) years and 86% self-reported as non-Hispanic White. We found little overlap between screening recommendations based on PV status vs. BCSC-PRS. In women with a high-penetrance PV, 1.3% (3/234) would have received a q6 screening recommendation based on BCSC-PRS. In women with a moderate-penetrance PV, 33% (92/278) were assigned to q6 screening, of whom 6.5% (6/92) would have received the same assignment under BCSC-PRS. Additionally, 65% (182/278) were assigned to yearly mammogram, of whom 2.2% (4/182) would have received the same assignment under BCSC-PRS. In women with PVs aged 40-49, 67% (187/280) would have been recommended no screening until age 50 based on BCSC-PRS. In women with PVs aged 50-74, 90% (390/432) would have been recommended biennial screening. Conclusions: Most women with PVs in BC genes would not have otherwise been recommended for enhanced screening based on clinical and PRS risk. Our results highlight the importance of testing for PVs as a cornerstone of risk-based screening on the population level. Future studies will examine opportunities for risk reduction as we integrate genetic and non-genetic risk factors. Clinical trial information: NCT02620852 .