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Hybrid deep learning and ES-MDA for pressure transient inversion in radial composite reservoirs

Methylation marks breast cancer metastasis: The roles of m6A-modified miRNAs and lncRNAs

A propensity score–matched real-world analysis of immune checkpoint inhibitors in melanoma patients with autoimmune disease.

9594 Background: Immune checkpoint inhibitors (ICIs) are foundational in the treatment of melanoma. However, patients with pre-existing autoimmune diseases (AD) have been excluded from pivotal ICI clinical trials and remain underrepresented in real-world outcome data. We conducted a propensity score–matched cohort study to evaluate the impact of pre-existing AD on clinical outcomes among melanoma patients treated with ICIs. Methods: A retrospective cohort study was performed using the TriNetX Research Network, including adult patients with melanoma treated with ICIs. ICI regimens included PD-1, PD-L1, and CTLA-4–based therapies. Patients with documented pre-existing AD were compared with patients without AD using 1:1 propensity score matching (PSM) for demographics, baseline corticosteroid use, laboratory values, and comorbidities. Outcomes included overall survival (OS) at 1 and 3 years; infections, corticosteroid exposure, and non-steroidal immunosuppressant exposure within 90 days of ICI initiation; and immune-related adverse events (irAEs), analyzed as a composite outcome and stratified by organ system (cardiac, pulmonary, endocrine, and dermatologic) within 180 days. Outcomes were assessed using hazard ratios (HRs), risk ratios (RRs), and 95% confidence intervals (CIs). Results: A total of 21,236 patients met inclusion criteria, including 3,372 with pre-existing AD and 17,863 without. After PSM, 3,372 patients were included in each cohort. Patients with AD demonstrated improved overall survival at both 1 and 3 years compared with those without AD (1-year HR 0.70, 95% CI 0.62-0.79; 3-year HR 0.76, 95% CI 0.70-0.84). Patients with AD were at increased risk for composite irAEs (RR 1.66, 95% CI 1.47–1.87). Organ-specific analyses demonstrated higher risks of cardiac (RR 3.29, 95% CI 2.02–5.34), endocrine (RR 1.48, 95% CI 1.22–1.81), and dermatologic irAEs (RR 1.46, 95% CI 1.22–1.73) among patients with AD. Patients with AD also had higher rates of corticosteroid (RR 1.23, 95% CI 1.18–1.28) and non-steroidal immunosuppressant exposure (RR 4.96, 95% CI 3.73–6.61), as well as increased risk of infection (RR 1.28, 95% CI 1.13–1.44). Conclusions: In this large real-world analysis, melanoma patients with pre-existing AD treated with ICIs demonstrated improved overall survival despite increased irAEs, immunosuppressant exposure, and infection. These findings challenge excluding patients with AD from receiving ICI therapy and support inclusion in future clinical trials. Outcome AD[n= 3,372] No-AD[n= 3,372] HR/RR [95% CI] 1-year OS 85.2% 79.8% 0.70 [0.62-0.79] 3-year OS 71.1% 65.2% 0.76 [0.70-0.84] Any irAE (180 days) 19.6% 11.8% 1.66 [1.47-1.87] Cardiac irAE 2.1% 0.6% 3.29 [2.02-5.34] Pulmonary irAE 0.8% 0.6% 1.34 [0.76-2.35] Endocrine irAE 7.0% 4.7% 1.48 [1.22-1.81] Dermatologic irAE 9.2% 6.3% 1.46 [1.22-1.73] Infection (90 days) 15.9% 12.6% 1.28 [1.13-1.44]

Changes in the incidence of second malignant neoplasms in neuroblastoma over time: An updated SEER database analysis.

10040 Background: To investigate changes in the incidence of second malignant neoplasms (SMN) for patients with neuroblastoma in the era of anti-GD2 immunotherapy, we analyzed patients from the SEER database according to four treatment eras (1: 1975–1989, 2: 1990–1996, 3: 1997–2010, 4: 2011–2018) corresponding to the introduction of multi-agent chemotherapy, risk-based treatment, stem cell transplant, and GD2-directed immunotherapy. We hypothesized that while the GD2-directed immunotherapy would not increase the incidence of SMNs for patients with neuroblastoma, the standardization of tandem autologous transplant would. Methods: The SEER database was assessed for patients younger than 30 years of age with neuroblastoma (ICD-O-3 9500) or ganglioneuroblastoma (ICD-O-3 9490). Patient demographic information and characteristics were assessed, including age at diagnosis, sex, race, histology, year of diagnosis, and extent of disease. Data about delivery of chemotherapy or radiotherapy were collected when available. Statistics including the cumulative incidence of SMN, standardized incidence ratios (SIRs), and rates of SMNs between patients in different eras were calculated. Results: The analytic cohort included 4,491 patients. Eighty-four patients (1.9%) developed a SMN with a median latency of 10 years. The SIR of all SMNs was 5.5 (95% CI 4.4-9.0). The majority of SMNs were hematologic (n=23; SIR 18.5, 95% CI 11.7-87.0), followed by kidney cancer (n=14; SIR 28, 95% CI 15.2-309.1) and thyroid cancer (n=12; SIR 11.2, 95% CI 5.8-58.6). Patients who developed a SMN were more likely to have received radiation than those who did not (39.3% versus 24.7%; p=0.002). There was no significant difference in median age, sex, race, or ethnicity between patients who did or did not develop a SMN. The cumulative incidence of SMN at 30 years from diagnosis for high-risk patients was 4.1% (95% CI 2.63-5.56) compared to 1.6% (95% CI 1.07-2.12) in non-high-risk patients. There was a trend toward increasing SIRs over time; in Era 1: the SIR was 3.4, with a 95% CI 2.2-7.0; in Era 2: the SIR was 3.2, with a 95% CI 1.4-9.9; in Era 3: the SIR was 8.7, with a 95% CI 6.3-20.3; and in Era 4: 9.2, 95% CI 4.8-42.1. Conclusions: High-risk neuroblastoma patients continue to suffer from high rates of SMNs compared to non-high risk neuroblastoma patients in the current era of GD2-directed immunotherapy. Using standardized incidence ratios, there is a trend toward increasing rates of SMNs in our cohort compared to the general population. This increase may be due to the continued addition of cytotoxic therapy. Ongoing monitoring and research into treatment-associated toxicities is needed for neuroblastoma survivors in the modern era of therapy.

Real-world impact of metabolic, renal, and demographic factors on overall survival in well- to moderately differentiated gastrointestinal and pancreatic neuroendocrine tumors.

e16326 Background: Well- to moderately differentiated gastrointestinal and pancreatic neuroendocrine tumors (NETs) show substantial heterogeneity in clinical outcomes. While tumor-related characteristics are established prognostic factors, the impact of patient-level comorbidities, metabolic factors, and sociodemographic characteristics on overall survival (OS) remains incompletely described. We evaluated OS across clinical, metabolic, renal, and demographic subgroups in a real- world cohort of patients with well- to moderately differentiated NETs. Methods: We conducted a retrospective cohort study using a harmonized clinical dataset spanning diagnosis, physical assessment, laboratory, and demographic domains. The cohort included adult patients with well- to moderately differentiated NETs of pancreatic and gastrointestinal origin; poorly differentiated tumors were excluded. Baseline characteristics, including body mass index (BMI, categorized as < 25 vs. ≥25 kg/m²), smoking status (ever vs. never), age at primary diagnosis, and race/ethnicity, were extracted. Advanced kidney disease (AKD) was defined as serum creatinine > 1.5 mg/dL on ≥2 occasions. OS was estimated with the Kaplan-Meier method, and differences were assessed with the log-rank test. Results: The cohort included 132 patients (Oncology Research Information Exchange Network, ORIEN). Overall survival was significantly worse in patients aged ≥50 years, with a shorter median OS than in patients younger than 50 years. For patients who were 50 or older at primary diagnosis, the median overall survival was 14.46 years, whereas for those younger than 50, the median OS was not reached(p = 0.046). There was no significant difference in median OS based on other clinical factors, including BMI, smoking status, advanced kidney disease, and race/ethnicity. Conclusions: In this real-world analysis of patients with GEP-NETs, age was the dominant predictor of overall survival.Traditional metabolic and renal risk factors did not demonstrate significant prognostic value in this cohort, suggesting that tumor biology or age-related background mortality may outweigh these comorbidities in this setting. Future studies utilizing larger, multi-institutional datasets are warranted to perform multivariate adjustments and isolate disease-specific survival outcomes.

Impact of first-line <i>EGFR</i> TKI dose reduction on survival and treatment sequencing in metastatic <i>EGFR</i> -mutant non–small cell lung cancer: A real-world cohort study.

e20746 Background: Dose reduction during first-line EGFR tyrosine kinase inhibitor (TKI) therapy is common in metastatic EGFR -mutant non–small cell lung cancer (NSCLC), particularly in older patients and those experiencing toxicity. However, the oncologic consequences of dose modification including its effect on survival, treatment durability, and ability to receive subsequent therapy remain unclear. We evaluated the association between first-line EGFR TKI dose reduction and clinical outcomes in a real-world cohort. Methods: We conducted a retrospective cohort study of patients with EGFR -mutated metastatic NSCLC treated with first-line EG FR TKI therapy. Primary endpoints were progression-free survival (PFS) and overall survival (OS), measured from initiation of first-line therapy. Secondary endpoints included time to treatment discontinuation (TTD) and receipt of second-line (2L) systemic therapy. Dose reduction were analyzed as binary characteristics. Survival outcomes were estimated using Kaplan–Meier methods and multivariable Cox regression. Receipt of 2L therapy was evaluated using logistic regression among patients who discontinued first-line therapy. Models were adjusted for age, ECOG performance status (PS), and EGFR TKI type. Results: Among 112 patients, median age was 70 years, and 36% were aged ≥75 years. First-line EGFR TKIs included osimertinib (57%), erlotinib (30%), and afatinib (13%). Dose reduction was more frequent among patients aged ≥75 years compared with those &lt; 75 years (32% vs 10%, p = 0.01). In multivariable Cox models adjusting for age, PS, and TKI generation, first-line EGFR TKI dose reduction was not associated with worse overall survival (HR 1.86, 95% CI 0.72-4.77), progression-free survival (HR 1.45, 95% CI 0.68-1.90), or time to treatment discontinuation (HR 1.47, 95% CI 0.74-2.8). Among patients who discontinued first-line EGFR TKI therapy, dose reduction was also not associated with lower odds of receiving second-line treatment (OR 0.13, 95% CI 0.01-1.07). In contrast, ECOG ≥2 remained independently associated with worse outcomes across endpoints, while age ≥75 was not prognostic. Conclusions: In this real-world EGFR -mutant NSCLC cohort, first-line EGFR TKI dose reduction was not associated with inferior survival, reduced treatment durability, or diminished access to subsequent therapy. Performance status, not age or dose modification, was the dominant predictor of outcomes. These findings support individualized dose adjustments during EGFR TKI therapy when clinically indicated, without concern for compromising oncologic efficacy or future treatment opportunities.

Genomic landscape of <i>ERBB3</i> alterations in 5,416 metastatic solid tumors: Real-world evidence regarding biomarker-agnostic ADC strategies.

3090 Background: While ERBB2 (HER2) is a well-established therapeutic target, the clinical significance and genomic landscape of ERBB3 (HER3) across diverse solid tumors are less defined. As HER3 emerges as a critical mediator of resistance and a target for novel antibody-drug conjugates (ADCs), characterizing its genomic alterations in a real-world setting is essential to refine therapeutic positioning. Methods: We analyzed clinical next-generation sequencing (NGS) data (Illumina TSO 500 or Oncomine Comprehensive Assay Plus) from 5,416 patients with metastatic solid tumors at a single tertiary center (Samsung Medical Center) between 2019 and 2025. ERBB3 alterations were categorized into mutations (SNVs/indels, VAF ≥2%) and amplifications (copy number [CN] ≥4). Results: ERBB3 alterations were identified in 12.9% (697/5,416) of patients. The prevalence was overwhelmingly driven by mutations (12.3%), while amplifications were rare (0.6%). The highest mutation frequencies were observed in: Urothelial carcinoma, 18.2%; Malignancy of unknown origin, 16.3%; and Biliary tract cancer, 15.7%. The most frequent variants were K498I (Domain IV) and R1127H (C-terminal tail). Known oncogenic hotspots (V104, A232V, G284R, E928G) were present but not dominant. Notably, the ERBB3-mutated cohort exhibited high co-mutation rates with canonical drivers: TP53 (66%), APC (35%), and KRAS (31%). In common GI cancers, ERBB3 mutations frequently co-occurred with APC and KRAS, suggesting they often act as "passenger" or secondary events rather than primary drivers. High-level amplifications (CN ≥8) were rare (&lt;0.1%) and appeared in isolated cases across various histologies. Conclusions: ERBB3 alterations are relatively common (12.9%) in metastatic solid tumors but are characterized by a diverse mutational landscape rather than focal amplifications. The high frequency of co-occurring canonical drivers suggests that HER3 primarily functions as a resistance hub or facilitator in these tumors. These real-world data provide a strong genomic rationale for biomarker-agnostic ADC strategies (targeting HER3 protein expression) rather than mutation-specific approaches in most ERBB3-altered solid tumors.

ROCKET-CLL: A randomized, open-label, multicenter, phase 3 study of rocbrutinib (LP-168) versus pirtobrutinib in covalent BTK inhibitor (cBTKi) in pretreated relapsed or refractory (R/R) chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL).

TPS7100 Background: Bruton tyrosine kinase covalent inhibitors (cBTKi) have been transformative in CLL treatment. Despite achieving extended remissions, in most patients disease still relapses despite cBTKi therapy, often associated with BTK C481 mutations. Non-covalent BTKi (ncBTKi), including pirtobrutinib, can overcome this resistance (Sharman et al. ASCO . 2025). Pirtobrutinib received FDA approval in Dec 2025, for R/R CLL/CLL patients pretreated with cBTKi. Rocbrutinib (LP-168) is a highly selective next-generation BTKi that can covalently bind wild-type and gatekeeper mutations (T474X, commonly seen in patients relapsed after pirtobrutinib) and non-covalently target C481-mutated BTK , with preclinical efficacy in treatment-naïve and BTKi-resistant CLL (Gordon et al. IWCLL . 2025). In the rocbrutinib phase 1 trial (NCT04775745), encouraging safety and efficacy have been observed in CLL patients with prior exposure to BTKi and/or BCL2 inhibitor (BCL2i) (Woyach et al. Blood. 2025). Presented here is the design of a phase 3 trial aiming to compare the efficacy of rocbrutinib versus pirtobrutinib in cBTKi-pretreated R/R CLL/SLL patients. Methods: ROCKET-CLL (NCT07342478) is a randomized, open-label, multicenter, phase 3 study comparing rocbrutinib (Arm 1) to pirtobrutinib (Arm 2) in R/R CLL/SLL subjects who previously received treatments including covalent BTKi. Eligible subjects must require treatment per 2018 iwCLL criteria, have measurable lesions by CT, an ECOG performance score of 0-2, and adequate hematologic and other organ functions. About 306 subjects will be randomized 1:1 based on stratification factors such as 17p deletion/ TP53 mutation presence, reasons for discontinuing prior cBTKi, prior BCL2i treatment, and geographic region. Participants assigned to each arm will receive rocbrutinib (200 mg QD) or pirtobrutinib (200 mg QD) tablets continuously until disease progression, unacceptable toxicity, withdrawal, or other study discontinuation criteria are met. The primary endpoint is progression-free survival (PFS), assessed by an independent review committee (IRC) per iwCLL 2018 criteria with CLL (Hallek et al. 2018) and Lugano 2014 criteria with SLL (Cheson et al. 2014). Important secondary endpoints include overall survival (OS), time to next treatment (TTNT), event-free survival (EFS), overall response rate (ORR), duration of response (DOR), PFS assessed by investigator (INV), concordance between IRC and INV PFS, safety and tolerability, and population PK. Exploratory endpoints include health-related quality of life and biomarker assessment. Recruitment is ongoing. Clinical trial information: NCT07342478 .

Effect of pimicotinib on tumor response and physical function (PF) by tumor location in patients with tenosynovial giant cell tumor (TGCT): Results from the phase 3 MANEUVER trial.

11567 Background: TGCT is a rare, locally-aggressive, soft-tissue tumor driven by colony-stimulating factor-1 (CSF-1) overproduction, often leading to impaired PF. Pimicotinib (pimi), an oral, highly-selective CSF-1 receptor inhibitor, demonstrated robust tumor responses, clinically meaningful symptomatic and functional improvements, and a tolerable safety profile in patients (pts) with TGCT in the global Phase 3 MANEUVER trial (NCT05804045). Here, we report the effects of pimi on tumor response and PF in joints most commonly affected by TGCT. Methods: In MANEUVER, symptomatic adult pts with unresectable TGCT were randomized 2:1 to once-daily pimi 50 mg or placebo for 24 weeks (Part 1). After Part 1, eligible pts received open-label pimi for 24 weeks (Part 2), followed by an ongoing long-term extension period (Part 3). Longer-term objective response rate (ORR) by blinded independent review committee (BIRC) per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1, Range of Motion (ROM) responses, and Patient-Reported Outcomes Measurement Information System-PF (PROMIS-PF) scores from Part 1 to Part 3, up to data cut-off, are reported by tumor location for pts randomized to pimi in Part 1. Results: At baseline, 63 pts were randomized to pimi; 71.4% were female and median age was 41.0 years (range 18–69). Median follow-up was 14.3 months and median treatment duration was 14.2 months. Most pts had diffuse TGCT (84.1%), with an affected lower extremity (85.7%), particularly the knee (52.4%). Tumor responses to pimi were comparable for localized (n=8) and diffuse (n=53) TGCT based on ORR by BIRC per RECIST v1.1 (95% CI): 87.5% (47.3, 99.7) vs 75.5% (61.7, 86.2), respectively. ORRs (95% CI) were comparable for pts with lower extremity (n=54) tumors and upper extremity (n=9) tumors: 75.9% (62.4, 86.5) vs 77.8% (40.0, 97.2), respectively, and for knee tumors (n=33) vs other (n=30) locations: 75.8% (57.7, 88.9) vs 76.7% (57.7, 90.1), respectively. Knee ROM improved from baseline to Week 49 (mean change: 8.9 [SD 8.4]). PROMIS-PF scores for lower extremity measures such as walking, climbing stairs, standing, and bending/kneeling improved from baseline (n=54) to Week 49 (n=43) (Table). Conclusions: Pimi provided sustained, clinically meaningful benefits in pts with TGCT, including durable tumor shrinkage and improved ROM and PF, regardless of tumor location. These results support pimi as an effective treatment option for patients with unresectable TGCT. Clinical trial information: NCT05804045 . Longer-term PROMIS-PF scores per item from baseline to week 49. PROMIS-PF score a Mean (SD) Baseline(N=54) Week 49 (N=43) Walk for ≥15 minutes 3.9 (1.0) 4.6 (0.6) Climb stairs 3.3 (1.1) 4.2 (0.8) Stand for 1 hour 2.9 (1.2) 3.7 (1.3) Bend, kneel, or stoop 2.7 (1.3) 3.6 (1.2) a 1-Unable to do; 2-With much difficulty; 3-With some difficulty; 4-With a little difficulty; 5-Without any difficulty.

Heterogeneity in biomarkers for advanced gastric cancer, gastroesophageal junction cancer, and esophageal adenocarcinoma (GC/GEJC/EAC) across regions: Insights from CheckMate-649.

4056 Background: In CheckMate 649, first-line nivolumab plus chemotherapy showed improved clinical efficacy vs chemotherapy in patients (pts) with advanced GC/GEJC/EAC, with varied benefit across regions in a subgroup analysis. To identify biomarkers predictive of differential efficacy outcomes, we did post hoc exploratory biomarker analyses by region. Methods: Post hoc exploratory analyses were done with whole-exome sequencing (WES) and RNA-seq of baseline tumor tissue. Pts were grouped by region: China (CN), Asia (including CN), United States + Canada + European Union (UCE), Latin America (LA). For WES-evaluable pts, gene alterations were profiled and pts grouped into genomic subtypes: chromosomal instability (CIN), genomically stable (GS), hypermutated (H), and Epstein–Barr virus (EBV)-positive. Gene expression signatures (GES) related to mitogen-activated protein kinase (MAPK) pathway, stroma, and angiogenesis were assessed by RNA-seq, and pts were stratified into tertiles based on GES score: high, medium, or low. Results: Of 1512 pts randomized, 647 were WES-evaluable (79, 141, 351, 155 in CN, Asia, UCE, and LA, respectively) and 769 RNA-evaluable (50, 106, 423, 240, respectively). A numerically lower proportion of CIN subtype and higher proportion of EBV subtype was seen in LA vs other regions (Table). Percentage (%) of select gene alterations was generally comparable across regions: of note, there was numerically higher % of altered FGFR2 (10%) in CN, altered TP53 (58%) , KRAS (16%) , CDKN2A (11%), and CDH1 (7%) in UCE, and altered PIK3CA (10%) and ERBB2 (22%) in LA. By contrast, there was numerically lower % of altered EGFR (4%) in Asia and altered ARID1A (8%) in LA. GES profile was broadly similar across regions, with numerically higher % of MAPK-high subgroup in UCE, stroma-medium/low subgroup in LA, and angiogenesis-low subgroup in CN (Table). Conclusions: While the biomarker profile was largely comparable across regions, differential features were noted for certain subgroups; clinical utility of these biomarkers requires validation in future trials. Clinical trial information: NCT02872116 . Regions CN Asia(including CN) UCE LA Genomic subtypes CIN 53 (67) 86 (61) 223 (64) 81 (52) GS 22 (28) 47 (33) 99 (28) 49 (32) H 4 (5) 6 (4) 18 (5) 6 (4) EBV 0 2 (1) 11 (3) 19 (12) GES 5-gene MAPK HighMediumLow 15 (30)13 (26)22 (44) 31 (29)29 (27)46 (43) 145 (34)153 (36)125 (30) 74 (31)79 (33)87 (36) 15-gene stroma HighMediumLow 20 (40)11 (22)19 (38) 38 (36)34 (32)34 (32) 151 (36)138 (33)134 (32) 70 (29)79 (33)91 (38) 5-gene angiogenesis HighMediumLow 15 (30)14 (28)21 (42) 35 (33)34 (32)37 (35) 137 (32)138 (33)148 (35) 81 (34)89 (37)70 (29) Data are n (%). % was calculated as events divided by number of WES- or RNA-seq–evaluable pts.

Telehealth visits to support extended dosing of pembrolizumab and reduce health care visits: A pragmatic trial.

1515 Background: Single agent pembrolizumab is standardly administered every 3 weeks (q3wk). Although extended interval dosing every 6 weeks (q6wk) was approved during the pandemic, most oncologists (65%) prefer q3-week dosing to monitor and mitigate immune-related adverse events (irAEs). We hypothesized that telehealth (TH)-enabled safety monitoring may facilitate broader adoption of q6 week dosing with reduced in-person health care visits while maintaining safety and patient experience. Methods: MAking Telehealth Delivery of Cancer Care at Home Effective and Safe for Immunotherapy (MATCHES-IO) is a single-arm pragmatic trial among patients with solid tumors receiving single-agent pembrolizumab. The intervention consisted of q6-week in-person pembrolizumab infusions with interim (eg. weeks 3,9,15) telehealth toxicity assessments during the first 6 months of therapy. Intervention components included a TH clinician visit, home phlebotomy, and biometric monitoring. The primary outcome was the number of days with an in-person health care facility visit, ascertained from the electronic health record. Participants were compared to a contemporaneous matched cohort receiving standard q3-week pembrolizumab, matched 1:1 on cancer type, stage (I–III vs IV), and age (15-year bands). Safety was evaluated by comparing irAEs requiring steroid use. Patient experience was assessed using a survey that included likelihood to recommend the intervention. Results: Between May 2023 and February 2025, 60 patients were enrolled (median age 69.5 [range: 25-85], 38% female, 78% white). Cancer diagnoses included thoracic (52%), genitourinary (30%), and melanoma (18%) in cases and controls. In matched analyses, there was a 3.5-day difference in total healthcare facility contact days between cases and controls (median 8.5 vs. 12.0, p = 0.14) that did not achieve statistical significance. Rates of irAEs requiring steroids were similar between groups (25.0% vs. 27.1%, p = 0.84). Fifty-two patients (87%) in the intervention group completed a patient experience survey. The median likelihood to recommend score was 10 (Q1,Q3: 8.0, 10.0). Most respondents (96%) perceived a benefit from the telehealth platform, including saved time (85%), increased convenience for patients (75%) and caregivers (44%), and cost savings (52%). Conclusions: Extended interval pembrolizumab supported by TH-enabled toxicity monitoring with remote phlebotomy and biometric assessments was associated with reduced in-person health care facility days but did not achieve the significance threshold. The intervention was associated with high patient satisfaction and no increase in irAEs. These results may address clinicians’ concerns about the safety of q6 week immunotherapy dosing and inform future care-delivery strategies integrating telehealth with immunotherapy treatment.

Real-world comparative outcomes of including levetiracetam with standard treatment in glioblastoma multiforme: A multi-center retrospective cohort study.

e14055 Background: Despite standard therapy temozolamide (TMZ), overall survival in Glioblastoma multiforme (GBM) remains poor. Several studies have suggested levetiracetam (LEV) may enhance survival and outcomes, but its use remains controversial due to conflicting studies. This is a real world study using the TriNetX database to evaluate whether adding LEV to TMZ improves survival. Methods: This retrospective study used the TriNetX database (January 2005 to December 2024) to evaluate adult patients with GBM. Outcomes were compared between patients receiving TMZ only vs TMZ and LEV. Patients underwent 1:1 propensity matching on age at index, race, comorbidities, and treatment history. Overall survival (OS) was compared using a Kaplan-Meier survival analysis while risk differences and z-tests were used to compare cytopenia and rehospitalization outcomes. Results: After matching, each cohort was reduced to 401 patients, achieving demographic balance as follows: age (mean 60.5 ± 12.5 vs 60.8 ± 13.8), sex (56.9% male vs 57.4% male), and white race (83.0% vs 84.3%). Median OS was comparable in TMZ + LEV vs TMZ only groups (539 days vs 508 days, HR = 1.02, 95% CI: 0.84 - 1.23, p = 0.28), with survival probabilities of 15.4% and 16.9%, respectively, at the end of the time window. Severe cytopenia was significantly more common in the TMZ + LEV group (9% vs 4%, p = 0.004). Rehospitalization was more common in the TMZ + LEV group but did not reach statistical significance (13.22% vs 9.48%, Risk Difference 3.74% with 95% CI: 0.64 - 8.12, p = 0.095). Conclusions: In a propensity-matched real world cohort, levetiracetam use in combination with temozolamide was not associated with improved overall survival and was linked to a higher rate of severe cytopenia compared to temozolamide alone. These findings add real-world evidence to the existing literature, though limitations exist with retrospective studies thus supporting the need for additional prospective studies to clarify the impact of LEV on GBM outcomes.

Impact of body mass index on toxicity and outcomes after CD19-directed CAR-T therapy for non-Hodgkin lymphoma.

e19072 Background: CAR-T therapy has improved outcomes for patients with R/R B-cell lymphomas; however, in overweight and obese patients, retrospective studies have suggested an increase in inflammatory toxicities, thereby narrowing therapeutic index in this population. [Cordas dos Santos et al. Haematologica, 2022.] Considering &gt;70% of individuals have an elevated BMI in the US, additional real-world analysis is needed to further characterize the safety and efficacy of CAR-T therapy for these patients. Methods: This single-center, retrospective study compares safety and efficacy among patients with BMI ≥ 25 compared to patients with BMI &lt;25 treated with CD19 directed CAR-T cell therapy for non-Hodgkin lymphoma from 10/1/2018 to 4/14/2025. Results: A total of 77 patients treated with CD19 directed CAR-T therapy were included in the final analysis with an average BMI of 28.7 (17-53). 48 patients had a BMI ≥25 (median 32, range 25.24-53.12) while 29 had a BMI &lt;25 (median 23.5, range 17.07-24.9). Hypertension and diabetes were independently present in 57.1% and 23.4% of patients, respectively. 37.7% (29) of patients had BMI ≥ 25 and hypertension while 20.8% (16) patients had BMI ≥ 25 with diabetes. After controlling differences in CAR-T product used, there was no difference in rates of all-grade CRS (66.7% vs 69%, p=0.835) or ICANS (20.8% vs 20.7%, p=0.964) among patients with BMI ≥ 25 vs &lt;25, respectively. Likewise, there was no difference between G3-4 CRS (0 in both groups) and ICANS (6.3% vs 10.3%, p=0.67). There was no difference in rates of all-grade CRS in patients with BMI ≥ 25 with diabetes vs those without diabetes (25% vs 34.4%, p=0.48) or ICANS (37.5% vs 16.4%, p=0.06). Patients with BMI ≥ 25 and hypertension had no difference in rates of all-grade CRS (62.1% vs 70.8%, p=0.426) or ICANS (17.2% vs 22.9%, p=0.55) as well. When comparing efficacy, overall (89.6% vs 75%, p=0.11) &amp; complete (68.4% vs 31.6%, p=0.06) response rates were numerically higher in the high vs low BMI cohort, respectively. Furthermore, patients with elevated BMI had longer median PFS (27.53 vs 5.61 months, p= 0.0023) and OS (not reached vs 9.9 months, p &lt; 0.001). Conclusions: In this single-center analysis, BMI ≥25 was not associated with increased inflammatory toxicity following CD19 CAR-T therapy, contrasting with some prior reports. Toxicity was similar regardless of diabetes or hypertension being present, suggesting that BMI may be the primary factor driving these outcomes; however, conclusions are limited by sample size. Patients with BMI &lt;25 experienced inferior outcomes, potentially due to lower physiologic reserve and altered metabolic states that may affect both the tolerability and efficacy of therapy. The improved clinical outcomes in patients with BMI ≥25 align with emerging evidence of an "obesity paradox" in CAR-T therapy, though the mechanisms underlying this association remain unclear and warrant further investigation.

Real-world adoption of comprehensive genomic profiling in a national cohort of patients with resected stage I–III non–small cell lung cancer.

8043 Background: Comprehensive genomic profiling (CGP) is increasingly used in the multidisciplinary management of resectable NSCLC to identify candidates for targeted adjuvant therapies and clinical trials. NCCN and Veterans Affairs (VA) guidelines recommend selective – not universal – testing in early-stage disease, yet real-world use after surgery remains poorly described. Using the VA’s highly unique National Precision Oncology Program (NPOP), we evaluated trends in CGP uptake, factors associated with testing, and the biomarker landscape in early-stage NSCLC. Methods: We performed a retrospective cohort study of patients with resected pathologic stage I–III NSCLC (2019-2025) within the VA. CGP was defined as next-generation sequencing (NGS) of the primary tumor within 3 months of surgery. We assessed frequency of CGP and clinicodemographic factors associated with GCP via multivariable logistic regression. We also assessed the distribution of potentially actionable genomic alterations. Results: A total of 6,605 patients were included (4,686 [70.9%] stage I; 1,255 [19.0%] stage II; 664 [10.1%] stage III). Over the study period, 1,337 (20.2%) patients received NGS testing. CGP utilization increased over time (11.4% in 2019 to 25.8% in 2025), paralleling evolving recommendations regarding adjuvant targeted therapies. Of note, the GCP utilization rate among those with stage Ib-III NSCLC in 2025 was 54.9%. In multivariable models, factors associated with higher CGP use included former smoking status (adjusted hazard ratio [aHR] 1.19, 95% CI 1.02-1.40), never smoking status (aHR 1.31, 95% CI 1.05-1.65), robotic resection (aHR 1.82, 95% CI 1.52-2.18), higher stage (stage II: aHR 4.33, 95% CI 3.72-5.04; stage III: aHR 5.79, 95% CI 4.81-6.98), and more recent treatment year (aHR 1.25, 95% CI 1.20-1.30). Median time from surgery to CGP ordering was 25 days (IQR 10-67). Among tested tumors, key genomic alterations included EGFR exon 19 deletions (2.39%) and L858R (1.20%), ALK fusions (0.52%), KRAS G12C (10.62%), MET exon 14 skipping (2.02%), ERBB2 mutations (3.29%), BRAF V600E (1.05%), and ROS1 fusions (0.53%). Conclusions: In this national cohort, CGP use after resection of stage I–III NSCLC increased substantially over time, likely supported by the VA NPOP infrastructure. Testing patterns were largely guideline-concordant, with continued uptake within complex multidisciplinary pathways. These findings reinforce the real-world adoption of genomically informed decision-making in early-stage disease while highlighting opportunities to strengthen implementation and promote wide access to precision oncology.

Retrospective analysis of colorectal cancer mutations and their associated risk of oxaliplatin-induced peripheral neuropathy.

e24091 Background: Oxaliplatin-induced peripheral neuropathy (OIPN) presents a huge clinical challenge for patients and clinicians as reliable biomarkers to identify patients at risk of developing OIPN are lacking. Previous studies have focused on circulating molecules (e.g., neurofilament light chain) as potential biomarkers associated with OIPN risk in the post-chemotherapy period. Conversely, insufficient investigations have concentrated on the potential effects of the tumor itself (pre-chemotherapy) and OIPN. In order to address this gap, we sought to determine whether there was a relationship between colorectal cancer (CRC) and OIPN. Methods: This is a retrospective cohort study enrolling patients with CRC (any stage) from 2013-2024 with clinically documented OIPN by comprehensive medical record review documenting demographic and other clinical features. OIPN was defined as “cold sensitivity”, “numbness” “tingling” or “neuropathy” and/or dose reduction, delay or discontinuation as a result of OIPN symptoms. Our study leveraged routine primary tumor DNA sequencing of CRC patients treated at AHWFBCCC (n=156) by FoundationOneCDx testing, which analyzes over 360 tumor mutations. Results: We found that patients with OIPN (n=123) received a higher cumulative dose of oxaliplatin and have a higher proportion of non-smokers compared to current smokers than non-OIPN patients (n=33). While we did not find any single mutation associated with OIPN, notably, we observed that patients with a low number of primary tumor mutations (&lt;11) have an increased risk of developing OIPN compared to patients harboring a high number of tumor mutations (≥11) (p = 0.0138) after adjusting for race, age, sex, oxaliplatin cumulative dose, and smoking status. Using ROC Curve analysis, we also found that number of mutations was promising as a predictive marker for OIPN (AUC = 0.668). We next aimed to ascertain how these mutations potentially function together and performed cancer pathway analysis comparing patients by OIPN status. Our analysis revealed that mutations in the Notch and TGFβ pathway were enriched in patients without OIPN. Conclusions: Our findings suggest, for the first time, that the primary tumor mutational profiles of patients with and without OIPN differ in their mutation number and associated pathways associated. We speculate that a low number of tumor mutations and/or inactive pathways may trigger immune cell activation to induce pro-inflammatory cytokine release that damages nerves, resulting in OIPN, although mechanistic studies are warranted. Our studies indicate harboring less tumor mutations may be a factor in altering the risk of developing OIPN and thus routine tumor sequencing has the potential to be utilized as an OIPN predictive biomarker.

Rab11 family interacting proteins as regulators of T cell recognition and infiltration in triple negative breast cancer.

2555 Background: Triple negative breast cancer (TNBC) accounts for 10-15% of all breast cancer cases and has the worst prognosis (5 year relative survival rate of 78%). TNBC is defined by absent estrogen and progesterone receptors and lack of HER2 amplification. First-line treatment for metastatic TNBC has evolved in the past several years to include immunotherapy for PD-L1+ patients. Recent NCCN guidelines recommend antibody-drug conjugate (ADC) therapy as first line treatment for metastatic TNBC regardless of PD-L1 positivity. ADCs target cell surface proteins that are abundant on tumors and sparse on healthy cells, delivering cytotoxic payloads selectively to the tumor. ADC efficacy depends on surface localization of target antigens, whose localization is dictated by endosomal trafficking via Rab GTPases. We showed that Rab11b-mediated endosomal trafficking is required for breast cancer brain metastasis. Here we investigate how trafficking-mediated control of the cell surface dictates immune recognition and response. Methods: Using a CRISPR screen we found that Rab11 family interacting proteins, Rab11fip2 and Rab11fip3, are required for immunogenic breast cancer cells to be recognized by CD8+ T cells. Flow cytometry revealed that the loss of recognition is not due to changes in surface PD-L1 or MHC/antigen presentation. Knockout of either Rab11fip did not change cell proliferation or tumor burden in immunocompromised animals, but led to significantly increased tumor growth in immunocompetent animals. This suggests that knockout of either Rab11fip causes loss of immune recognition to allow faster tumor growth while control tumors are restrained by the immune system. IHC analysis revealed a significant decrease of tumor infiltrating T cells in Rab11fipKO tumors. Interestingly, immune disruption is systemic, as splenic architecture is disrupted in Rab11fipKO tumor bearing mice. Results: Since the primary function of Rab11fips is to mediate trafficking of Rab11 cargo proteins, our results suggest that surface localization of these cargo proteins is required for immune cell recruitment, recognition, or activation. Conclusions: We are currently focused on identifying these cargo proteins, determining whether Rab11 controls trafficking of Trop-2 the target of several current ADCs, and characterizing Rab11 control of the T cell-cancer cell interaction in human breast cancer cell lines. Our work holds the promise of finding novel targets for ADCs and biomarkers for responsiveness to immunotherapy.

Long-term survival and biomarker analysis of neoadjuvant chemoradiotherapy with or without PD-1 antibody sintilimab in pMMR locally advanced rectal cancer: A randomized clinical trial.

3610 Background: We previously reported that adding sintilimab to neoadjuvant chemoradiotherapy (NACRT) significantly improved the complete response (CR) rate compared to NACRT in mismatch repair-proficient (pMMR) locally advanced rectal cancer (LARC) patients (44.8% vs. 26.9%; P = 0.031). Here, we present the long-term survival outcomes and exploratory biomarker analyses from this randomized trial. Methods: Between June 2020 and July 2022, a total of 134 patients with pMMR LARC were randomly assigned (1:1) to the experimental arm (NACRT plus sintilimab, n = 67) or the control arm (NACRT, n = 67). The primary endpoint was CR rate. Secondary endpoints included disease-free survival (DFS) and overall survival (OS). Survival analysis was estimated using the Kaplan-Meier method and compared using the log-rank test. Hazard ratios (HR) were calculated using the Cox proportional hazards model. Baseline tumor and blood samples were collected for whole exome sequencing. Results: With a median follow-up of 48.5 months, the experimental arm exhibited significantly superior 3-year DFS compared to the control arm (91.0% vs. 77.6%; HR = 0.37, 95% CI: 0.14-0.94, log-rank P = 0.030). Analysis of failure patterns showed lower rates of both local recurrence (1.5% [1/67] vs 3.0% [2/67] and distant metastases (9.0% [6/67] vs. 19.4%[13/67]) in the experimental arm. Notably, liver metastases were more frequent in the control arm (1.5% [1/67] vs. 9.0% [6/67]). Subgroup analyses identified a pronounced DFS benefit from combination therapy in patients aged &gt; 50 years (HR = 0.24, 95% CI: 0.07-0.86, P = 0.029) and those with extramural venous invasion (EMVI)-positive tumors (HR = 0.26, 95% CI: 0.09-0.81, P = 0.020). Notably, achieving a CR was consistently associated with a trend toward prolonged DFS in both the experimental (log-rank P = 0.129) and control arms (log-rank P = 0.145). In exploratory biomarker analysis, patients harboring MUC16 mutations in the experimental arm exhibited a trend toward improved DFS, although statistical significance was not reached (log-rank P = 0.318); conversely, no such trend was observed in the wild-type population (log-rank P = 0.496). The 3-year OS rates were 97.0% in both groups (log-rank P = 0.977). Conclusions: Adding PD-1 antibody to NACRT conferred a superior DFS benefit compared to NACRT in patients with pMMR LARC, particularly in older patients and those with EMVI-positive tumors, and potentially influenced the pattern of metastasis. MUC16 mutations warrant further investigation as a potential predictive biomarker for sensitivity to the combination therapy. Clinical trial information: NCT04304209 .

The effect of switching from ribociclib to palbociclib due to toxicity in hormone receptor–positive, HER-2–negative metastatic breast cancer: A real-world, multicenter, retrospective study.

e24144 Background: In metastatic hormone receptor (HR)-positive and HER-2-negative breast cancer, toxicity with CDK 4/6 inhibitors is seen at a rate that cannot be underestimated. We aimed to investigate the clinical effect of switching from ribociclib to palbociclib in patients who developed toxicity, whether there was a difference in progression-free survival (PFS), and whether toxicity persisted or new side effects developed after the switch. Methods: This retrospective and observational study includes participants from nine centers who were followed between September 2020 and September 2025. 1,392 patients were screened. Toxicity causes, drug-drug interactions (DDI), objective response rates (ORR), and PFS were examined. All statistical analyses were performed using IBM SPSS Statistics 25.0. Results: 44 patients were included in the study. All patients were female, with a median age of 57 (50,25-67,5). De novo metastatic disease was present in 30 (68,2%) patients, and 33 (75%) patients were postmenopausal. There were 34 (77.3%) patients treated with ribociclib in the first line treatment. The most common cause of switching was hepatotoxicity, accounting for 18 cases (40,9%). Cardiotoxicity was observed in 11 patients (25%), skin toxicity in 9 patients (20.5%), refractory grade 3 neutropenia in 2 patients (4.5%), nephrotoxicity in 3 patients (6.8%), and grade 3 anemia in 1 patient (2.2%).The median time to switching was 4.3 months. There was no statistically significant difference between DDI and switch time, p=0.118. The ORR in 31 patients was 70.9%, as the follow-up period was too short to evaluate response in 13 patients before toxicity. In 3 patients who switched from ribocicllib to palbociclib after toxicity, the response could not be evaluated due to the short duration of treatment. The ORR in 41 patients was 73.1%. The median (m) follow-up period was 23.9 months. The OS was not yet mature, as 11 patients (25%) had died. The mPFS in all patients was 29.9 (24.4-35.5) months. The PFS rate at month 24 was 65.3%. In patients with a switch in &lt;4.3 months (n:22), mPFS was 31.4 (24.1-38.8) months, while in patients with a switch in ≥ 4.3 months (n:22), mPFS was 28.4 (22.2-34.6) months, p=0.682 . When patients treated with ribociclib in the first line were evaluated, mPFS was 31.6 (23.6-39.6) months in those with a switch &lt;4.3 months (n:18), while in those with a switch ≥ 4.3 months (n:16) mPFS was 25.5 (20.1-31) months, p=0.618. Multivariate Cox regression analysis revealed that the timing of the switch did not affect the prognosis. Conclusions: In metastatic HR-positive and HER-2-negative breast cancer, when toxicity develops with ribociclib, switching to palbociclib should be considered instead of reducing the dose or discontinuing treatment, and it should be remembered that the toxicity will not continue.

Sepsis-related mortality in adults with liver and intrahepatic bile duct malignancies: A 25-year national analysis of trends and disparities, 1999-2023.

e16204 Background: Sepsis is a frequent and often terminal complication in patients with malignant neoplasms of the liver and intrahepatic bile ducts. Population-level trajectories and disparities in sepsis-related mortality among adults with liver malignancy have not been fully described. This study quantifies temporal, demographic, and geographic patterns in sepsis-related mortality among adults with liver malignancy in the United States from 1999 through 2023. Methods: We analyzed multiple-cause-of-death data from the CDC WONDER database from 1999–2023 for deaths among adults aged ≥25 years in which codes for ICD-10 for sepsis (A40–A41) and malignant neoplasm of the liver and intrahepatic bile ducts (C22) co-occurred. Age-adjusted mortality rates (AAMR) per 1,000,000 population were extracted. Temporal trends were assessed using Joinpoint regression to estimate annual percent change (APC) and average annual percent change (AAPC). Results: From 1999 to 2023, 24,924 sepsis-related deaths were recorded among adults with liver malignancy. The overall mean AAMR increased substantially from 2.41 in 1999 to 6.85 in 2023, representing an AAPC of 5.10% (95% CI: 4.83-5.36). Males experienced higher mortality (5.72) than females (2.72), though both sexes showed steep increases (AAPC: 5.18% vs. 4.91%). All racial groups demonstrated increasing mortality during the study period. Racial stratification revealed the highest mean AAMR among Non-Hispanic Asian or Pacific Islanders (8.88), followed by Hispanic or Latino (7.09) and Non-Hispanic Black or African Americans (6.48). Adults aged ≥65 years bore the greatest burden, with crude mortality rate rising from 7.85 in 1999 to 22.40 in 2023. Mortality rates remained consistently elevated for both the 65–85+ and 45–64 age groups during the study period. Metropolitan areas had a higher mean AAMR than non-metropolitan areas (3.93 vs. 2.94). Geographic disparities were pronounced, with states exhibiting the highest AAMRs in 2021-2023 including California (10.04), Washington (9.28), Texas (9.02), Kentucky (8.72), and Delaware (8.16); those with the lowest rates included West Virginia (3.85), North Carolina (4.35), Virginia (4.56) and Wisconsin (4.64). Regionally, the West had the highest mean AAMR at 5.14, followed by the Northeast (4.14), South (4.00), and Midwest (3.18). Most deaths occurred in inpatient medical facilities (84.5%). Conclusions: Sepsis-related mortality among adults with liver malignancy increased substantially over 25 years across most demographic and geographic strata. Pronounced disparities among Asian or Pacific Islander populations, males, older adults, and residents of Western states underscore the urgent need for targeted sepsis prevention strategies, early recognition protocols, and improved end-of-life care for patients with hepatobiliary malignancies.

A randomized phase II trial of mirvetuximab soravtansine in folate receptor alpha (FRα)–high recurrent ovarian cancer eligible for platinum-based chemotherapy (MIROVA/AGO-OVAR 2.34).

5506 Background: Mirvetuximab soravtansine (MIRV) has demonstrated single agent activity in patients with platinum-resistant ovarian cancer with FRα high expression. However, its activity and safety in combination with carboplatin has not been defined in platinum eligible patients so far. Methods: Randomized phase II trial comparing 6 cycles of carboplatin AUC5+MIRV 6 mg/kg AIBW every 3 weeks followed by MIRV versus 6 cycles of carboplatin combined with either paclitaxel, gemcitabine or pegylated liposomal doxorubicin followed by maintenance PARP inhibitor (PARPi) if applicable. All histologic subtypes were eligible with a platinum-free interval &gt;3 months and FRα high expression (≥75% with PS2+ scoring) confirmed by central laboratory. Prior PARPi therapy in BRCAmut patients was mandatory. Strata were BRCA-Status, TFIp and number of prior lines of chemotherapy. The primary endpoint was PFS. Results: In total, 145 patients were randomized. Of them, 112/145 (77.2%) patients had received prior bevacizumab and 97/145 (66.9%) had prior PARPi, 15.2% were BRCAmut. In the standard arm, 39.15% received PARPi as maintenance. Median PFS in the standard arm was 9.79 months versus 9.53 months in the experimental arm (p=0.996; HR=1.00; 95% CI: 0.68; 1.46). Conclusions: MIROVA/AGO-OVAR 2.34 is the first randomized trial evaluating the activity and safety of the combination of carboplatin with an antibody-drug conjugate in the setting of platinum-eligible relapsed ovarian cancer. The primary endpoint regarding improvement of PFS was not met. Further analysis will be presented. Clinical trial information: NCT04274426 .