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Application of unsupervised genetic clustering to identify biologically distinct cholangiocarcinoma subtypes with differential survival.

4025 Background: Cholangiocarcinoma (CCA) is a genetically heterogeneous malignancy for which current anatomic and histologic classifications inadequately predict survival. We hypothesized that unsupervised machine learning clustering of mutations and copy number alterations(CNA) could identify biologically distinct CCA subgroups with clinically meaningful differences in survival. Methods: Genomic and clinical data were obtained from the MSK cholangiocarcinoma dataset from cBioPortal. 790 patients with intrahepatic and extrahepatic CCA with available mutation and CNA data were included. Multiple unsupervised approaches were evaluated, including k-means, hierarchical clustering, non-negative matrix factorization, PCA–k-means, and UMAP–k-means. Model performance was assessed using silhouette scores, with UMAP–k-means (n=4 clusters) selected as the optimal method. Clusters were defined by dominant genetic alterations and compared for overall survival using Kaplan–Meier analysis with pairwise log-rank testing. Subgroup analyses included patients without curative-intent surgery and a young-onset cohort. Results: UMAP–k-means delineated four distinct genomic clusters ordered by progressively worse median survival. Cluster 1, defined by ARID1A or BAP1 mutations, demonstrated the most favorable survival outcomes. Cluster 2 consisted of tumors wild type for recurrent driver alterations. Cluster 3 was characterized by TP53 , KRAS , or IDH1 mutations. Cluster 4, defined by CDKN2A double deletion or ERBB2 amplification, exhibited the poorest median survival. Overall survival differed significantly across clusters, with all pairwise Kaplan–Meier comparisons reaching statistical significance except between clusters 1 and 2. These survival differences remained significant in patients who did not undergo curative-intent surgery. Notably, cluster 4 remained associated with significantly worse survival within the young-onset cohort. Conclusions: Unsupervised genomic clustering using UMAP–k-means identified biologically distinct subtypes of cholangiocarcinoma, with clinically significant survival differences that persist across surgical and age-based subgroups. These findings support future genomic subtyping as a prognostic framework and a rationale for biology-driven clinical trial stratification in cholangiocarcinoma. Unsupervised genetic clustering identifies biologically distinct cholangiocarcinoma subtypes with differential survival. Cluster Primary Genetic alterations N patients Median OS log-rank test P-value vs cluster 2 log-rank test P-value vs cluster 3 log-rank test P-value vs cluster 4 1 ARID1A or BAP1 mutant 120 28.0 0.308 <0.001 <0.001 2 Wild types 224 26.7 - 0.003 <0.001 3 TP53, KRAS or IDH1 mutant 319 22.0 - 0.002 4 CDKN2A deletion or ERBB2 amplification 127 16.9 -

Real-world efficacy and safety of iruplinalkib in <i>ALK</i> -positive advanced lung adenocarcinoma patients previously treated with lorlatinib.

e20730 Background: Treatment options after lorlatinib failure remain limited in patients with anaplastic lymphoma kinase ( ALK )-positive advanced lung adenocarcinoma (LUAD). Iruplinalkib (WX-0593) has shown systemic and intracranial activity. We report updated results with extended follow-up from a real-world study evaluating iruplinalkib in this setting. Methods: Patients with ALK -positive advanced LUAD who received iruplinalkib after progression on or intolerance to lorlatinib were included. The primary endpoint was real-world progression-free survival (rwPFS). Secondary endpoints included real-world objective response rate (rwORR), disease control rate (rwDCR), overall survival (OS), and safety. Data cutoff was December 31, 2025 (ChiCTR2600116971). Results: Sixteen heavily pretreated patients were included, with a median of 4 prior systemic therapy lines (range 2–7); 81.3% (13/16) had baseline brain metastases. Iruplinalkib was administered as monotherapy in 62.5% of patients , while 37.5% received combination therapies based on physician discretion. With a median follow-up of 15.8 months, the rwORR was 31.3% (5/16) and rwDCR was 87.5% (14/16). The median PFS was 12.4 months (95% CI: 7.66–NE). The median OS reached 22.1 months (95% CI: 22.1–NE), although OS data remain immature. Safety profiles were consistent with previous reports. Grade ≥3 treatment-related adverse events (TRAEs) occurred in 12.5% of patients, with no new safety signals observed. Conclusions: In this updated analysis, iruplinalkib demonstrated durable clinical efficacy in heavily pretreated ALK -positive LUAD patients progressing on lorlatinib, including those with a high burden of brain metastases. The median PFS of 12.4 months and OS of 22.1 months in a ≥ 4 th -line setting supports iruplinalkib as a promising salvage option. Clinical trial information: ChiCTR2600116971. Baseline characteristics and clinical outcomes. Parameters Results (N=16) Baseline Characteristics Age (median, range) 48.5 (34.00-63.00) Sex Male 6 (37.5%) Female 10 (62.5%) ECOG PS 0-1 12 (75.0%) ≥2 4 (25.0%) Baseline brain metastasis 13 (81.3%) Prior ALK TKIs Crizotinib + 2nd-generation TKIs + lorlatinib 13 (81.3%) 2nd-generation TKIs + lorlatinib 3 (18.8%) Prior 2nd-generation ALK TKI Aletinib 12 (75.0%) Ceritinib 6 (37.5%) Brigatinib 4 (25.0%) Ensartinib 5 (31.3%) Other Prior Therapies Prior chemotherapy 9 (56.3%) Prior anti-angiogenesis 10 (62.5%) Prior immune checkpoint inhibitor 2 (12.5%) Efficacy Partial response 5 (31.3%) Stable disease 9 (56.3%) Progressive disease 1 (6.3%) Not evaluated 1 (6.3%) Objective response rate (ORR) 31.3% (5/16) Disease control rate (DCR) 87.5% (14/16) Median PFS (95% CI) 12.4 months (7.66–NE) Median OS (95% CI) 22.1 months (22.1–NE) Safety Any grade TRAE 9 (56.3%) Grade ≥ 3 TRAE 2 (12.5%) TRAE leading to dose interruption/reduction/discontinuation 1 (6.3%) /0/0

Long-term safety results and adverse event (AE) management recommendations in patients with ER+/HER2− metastatic breast cancer (mBC) receiving prifetrastat, a first-in-class KAT6 inhibitor, at the recommended phase 3 dose (RP3D) of 5 mg once-daily (QD).

1068 Background: Prifetrastat (PF-07248144) is a first-in-class, potent, and selective inhibitor of the epigenetic modifiers KAT6A and KAT6B. In an ongoing phase 1/2a study (NCT04606446), prifetrastat has demonstrated encouraging antitumor activity and manageable safety when combined with fulvestrant (FUL) in patients with heavily pretreated ER+/HER2– mBC (Mukohara T, et al. Nat Med. 2024;30:2242-50). Here, we report comprehensive and long-term safety results and AE management recommendations after extended follow-up of patients receiving prifetrastat (± FUL) in this phase 1/2a study. Methods: This dose escalation (part 1)/expansion (part 2) study included patients with ER+/HER2– mBC whose disease progressed after prior treatment with a cyclin-dependent kinase 4/6 inhibitor (CDK4/6i) and endocrine therapy. In part 1, patients received prifetrastat at varying doses as monotherapy or in combination with 500 mg FUL. In part 2, patients received prifetrastat (± FUL) at the recommended dose for expansion (RDE; 5 mg QD) identified in part 1. Primary objectives were safety/tolerability assessment and RDE selection. Results: 5 mg QD prifetrastat was previously identified as the RDE and RP3D in combination with FUL based on safety, PK/PD, and antitumor activity. As of Oct 13, 2025, a total of 92 patients were treated at the 5 mg QD dose (43 as monotherapy and 49 in combination with FUL). The most common treatment-related AEs (TRAEs) were dysgeusia (84.8%; all grade [G] 1 [66.3%] or 2 [18.5%]), neutropenia (68.5%), and anemia (50.0%). Weight loss was reported infrequently as a TRAE (5.4%). The most common G3/4 TRAEs were neutropenia (G3, 34.8%; G4, 6.5%), anemia (G3, 15.2%; no G4), and leukopenia (G3, 12.0%; no G4); no G5 TRAEs were reported. TRAEs led to dose reductions in 45 (48.9%) patients, 75.6% (n = 34/45) of whom reduced their dose due to reversible neutropenia. TRAEs led to discontinuation in 2 patients (G2 neutropenia [n = 1]; G3 myocardial injury/troponin increased [n = 1]). G3/4 neutropenia was reversible and well-managed with dose modifications and supportive care. No febrile neutropenia was reported. Dysgeusia was managed with supportive care, including patient education, weight monitoring, and nutrition consultation, as clinically indicated. Dysgeusia did not lead to any treatment discontinuations or dose reductions. Conclusions: After extended follow-up of the phase 1/2a study, the RP3D of prifetrastat (5 mg QD) maintained a manageable safety profile when dose modifications and supportive care measures were implemented for AEs such as neutropenia and dysgeusia. These AE management strategies have been incorporated into the ongoing phase 3 study (KATSIS-1; NCT07062965) in patients with HR+/HER2− mBC after progression on CDK4/6i-based therapy. Clinical trial information: NCT04606446 .

Outcomes of second round PRRT in patients with progressive refractory stage IV neuroendocrine neoplasms (NEN).

e16331 Background: Ever since approval of PRRT for NEN in 2018, our institution has administered PRRT to around 700 patients. Seeing the rather excellent benefit – risk profile, we also trialed single or multiple repeat doses of PRRT in Stage IV patients who initially responded well but later progressed after their first PRRT round and who were either refractory to or contraindicated for other lines of therapies. The dosage, number, and interval between repeat doses was decided individually based on radiographic response and adverse effects. The aim of the study was to evaluate the safety and tolerability as well as value of the second round PRRT in this patient group. Methods: We retrospectively reviewed all patients who received a second round PRRT at our institution for refractory disease between 2018 to 2024. Multiple patient, disease, and treatment related parameters were collected, including demographic information, sites of disease, time and lines of therapies received, time points at which PRRT was received. Only patients who had both pre- and post-therapy scans within 3 months of starting/finishing second round PRRT were included. A fellowship-trained radiologist reanalyzed radiological response using RECIST 1.1. Results: Nine of a total of thirteen patients retreated met our inclusion criteria. Mean age of the study cohort was 68 yrs, 44% (4/9) were females, all ECOG 1-2, and they received up to 3 extra reduced doses of PRRT as mentioned in table 1. The average duration between the first and the second PRRT rounds was 36 +/- 14 months. 44% (4/9) patients achieved disease stability on the follow-up scans with two of them staying alive beyond 1.5 years from re-treatment. 56% (5/9) patients progressed on the first follow-up scans. Only 2 months of median CT follow-up was achieved due to mortality within 6 months for the larger segment of patients who showed refractory progression. There were not clinically significant hematologic or other adverse events. Conclusions: Second round PRRT is a safe and tolerable therapy for patients with progressive disease refractory to chemotherapy. Four out of nine patients demonstrated disease stability with two patients achieving substantial progression-free survival. Longer follow-ups are needed to assess long-term survival benefits. PRRT dosing of each patient and outcome. Patient Number and dosage (mCi) Radiographic response Outcome #1 4 – 200 &amp; 2- 100 each Progression Death from unknown reasons # 2 4- 200 &amp; 3- 100 each Progression Death from unknown reasons # 3 4 – 200&amp; 2 –100 Progression Death from unknown reasons #4 6 – 200 each Stable Death from NEN #5 4 – 200 &amp; 1-100 Stable Death from unknown reasons #6 4 – 200 &amp; 1-100 Stable Death from unknown reasons #7 4- 200 &amp;2-100 Stable Death from unknown reasons #8 4- 200 &amp;1-100 Progression Death from unknown reasons #9 4-200 &amp;1-100 progression Death from NEN

Respiratory failure in patients treated with immune checkpoint inhibitors.

e24169 Background: Immune checkpoint inhibitors (ICIs) are increasingly used across cancer types, yet the causes and outcomes of acute respiratory failure (ARF) in ICI-treated patients remain poorly defined. Although checkpoint inhibitor pneumonitis (CIP) is a recognized immune-related adverse event, its contribution to severe ARF and short-term outcomes is uncertain. Methods: We conducted a retrospective cohort study of adults treated with ICIs who developed ARF requiring ≥24 hours of non-invasive or invasive ventilatory support across five hospitals in a single health system (2017-2024). ARF etiology was determined by manual chart review with multidisciplinary adjudication to identify CIP. Clinical characteristics, cancer features, and outcomes were compared between CIP and non-CIP ARF. Cox proportional hazards models evaluated associations between CIP and mortality. Results: Among 197 patients with ICI-associated ARF, 29 (15%) were adjudicated as CIP-related and 168 (85%) had non-CIP etiologies. Median age was 66 years (IQR 59–74), and demographics were similar between groups. Lung cancer was more common in CIP than non-CIP ARF (62% vs 35%, p = 0.01). Time from first ICI exposure to ARF did not differ (median 112 vs 138 days, p = 0.44). CIP patients more often received non-invasive ventilation alone (69% vs 45%) and were less likely to require isolated invasive mechanical ventilation (3% vs 44%, p &lt; 0.01). CIP was associated with more severe hypoxemia (median SpO₂/FiO₂ 120 vs 148, p = 0.01) but less non-respiratory organ dysfunction (median SOFA 2 vs 5, p &lt; 0.01). Ninety-day mortality was 65.5% in CIP and 70.8% in non-CIP ARF (p = 0.56). CIP was not associated with 90-day mortality in adjusted analysis (HR 0.66, 95% CI 0.40-1.08). CIP was associated with lower in-hospital mortality (adjusted HR 0.43, 95% CI 0.21-0.88) and shorter time to hospital discharge (adjusted SHR 1.81, 95% CI 1.07-3.05). Conclusions: CIP accounted for a minority of ARF events after ICI therapy and was not associated with higher short-term mortality despite more severe hypoxemia. Outcomes following ARF appear driven more by underlying illness severity and cancer burden than by immune-mediated lung injury. Improved diagnostic precision may help guide immunosuppression and prognostication in this high-risk population. Causes of Acute Respiratory Failure (ARF) in ICI-treated patients. ARF Etiology n (%) Pneumonia 54 (27%) Progressive cancer 37 (19%) Volume overload 29 (15%) CIP 29 (15%) Aspiration 26 (13%) Sepsis / ARDS 9 (5%) Pulmonary embolism 9 (5%) Neuromuscular 3 (2%) Total 197 (100%)

AI-powered spatial tumor microenvironment analysis in metastatic microsatellite-stable colorectal cancer receiving immunotherapy.

2532 Background: Microsatellite-stable (MSS) colorectal cancer (CRC) is typically immune-cold, limiting the routine use of immune checkpoint inhibitors (ICIs). However, a subset of MSS CRC patients may still derive benefit from ICIs. Leveraging an AI-powered whole-slide image (WSI) analyzer applied to hematoxylin and eosin (H&amp;E)–stained slides, we sought to identify subsets of MSS CRC more likely to benefit from ICIs. Methods: Between August 2016 and May 2024, pretreatment H&amp;E–stained WSIs were collected from patients with metastatic MSS CRC treated at Asan Medical Center, Seoul, Korea. After quality control, 91 WSIs (93.8%) from 51 patients were included in the final analysis. Patients were treated with anti-PD-1/PD-L1 ICIs in clinical trials, with the majority treated in the third-line setting (n = 46, 90.2%). An AI-powered WSI analyzer (Lunit SCOPE IO, Lunit, Seoul, Korea) segmented cancer area (CA) and stromal area and identified tumor-infiltrating lymphocytes (TILs), tertiary lymphoid structures (TLS), fibroblasts, and endothelial cells within tumor tissue. We then evaluated the associations between CA-specific densities of TILs, macrophages, and endothelial cells, as well as the summed TLS area, and progression-free survival (PFS) and overall survival (OS). Results: Using maximally selected rank statistics based on PFS, patients were dichotomized into high and low groups according to the summed TLS area and the densities of TILs, macrophages, endothelial cells, and fibroblasts within the CA. Notably, patients with a high summed TLS area had significantly improved PFS and OS compared with those with a low TLS area (median PFS, 3.6 vs. 1.6 months; P=0.026; median OS, 11.6 vs. 6.6 months; P=0.024). High endothelial cell and fibroblast densities within the CA were not significantly associated with PFS (P=0.160, P=0.112, respectively), but were associated with worse OS, with a significant association for endothelial cells (median, 7.6 vs. 14.7 months; P=0.024) and a trend toward worse OS for fibroblasts (median, 8.9 vs. 12.2 months; P=0.056). Higher macrophage density within the CA showed a favorable trend toward improved PFS (median, 10.2 vs. 8.5 months, P=0.092), but was not associated with OS (P=0.399). In contrast, none of these biomarkers were associated with clinical outcomes in the first-line chemotherapy. Conclusions: Despite microsatellite-stable status, a higher summed TLS area was associated with improved progression-free and overall survival following immunotherapy, with endothelial cell and fibroblast densities providing additional prognostic information. AI-powered WSI analysis enabled effective stratification of these features.

BC3195, a novel ADC targeting cadherin-3 (CDH3): Preliminary results of a phase I study in patients with advanced solid malignancies (study BC3195-102).

3035 Background: Cadherin-3 (CDH3), a calcium-dependent adhesion glycoprotein, is overexpressed on lung, breast, ovarian, colorectal, pancreatic, head-neck and other malignancies, but expression on nonmalignant tissue is negligible. CDH3 is essential for cancer cell proliferative signaling and is associated with aggressiveness, invasiveness and poor prognosis. BC3195 is an antibody-drug conjugate (ADC) comprised of an antibody targeting CDH3, a cleavable linker and a monomethyl auristatin E (MMAE) payload. Methods: Two phase Ia/Ib studies of BC3195, whose objectives are to evaluate the safety, pharmacokinetics (PK) and preliminary antitumor activity of the ADC, are enrolling patients (pts) with advanced solid malignancies in the US (BC3195-102) and China (BC3195-101). In both studies, BC3195 is administered as a 1-hour (h) IV infusion every 3 weeks. In BC3195-102, dose escalation uses a BOIN design with pre-selected dose levels (DLs) of 1.8 and 2.4 mg/kg and an algorithm to explore lower or intermediate DLs based on safety. Results: As of data cut-off (Dec 30, 2025), 16 pts have been enrolled at DLs of 1.2 (3 pts), 1.5 (3 pts), 1.8 (9 pts), and 2.4 mg/kg (1 pt). Fourteen (87.5%) pts had received ≥3 prior treatment. Fatigue (81.3%) and stomatitis (62.5%) were the main adverse events (AEs). Three pts (18.8%) had Grade ≥3 AEs, two of which were Grade 3 stomatitis in the first week post-treatment of Cycle 1 at the 1.8 mg/kg DL of Cohort 1. The dose of BC3195 was subsequently de-escalated to 1.2 mg/kg and then re-escalated to 2.4 mg/kg along with preventative measures, which included ice chip mouth rinses, dexamethasone mouthwash, and B vitamins in the peri-treatment period, and topical steroids for any skin rash. There was no further stomatitis of Grade 3 severity after implementation of these measures; 1 pt had a Grade 3 rash in Cycle 2 at 1.5 mg/kg that responded rapidly to oral steroids. Neither ocular nor neurotoxicity have been noted. Of 16 pts evaluable for tumor response (RECISTv1.1), 3 partial responses occurred in heavily pretreated pts with HER+ breast cancer, prostate cancer, and fibrosarcoma, all of whom were treated at the 1.8 mg/kg DL. Preliminary PK results (1.2-1.8 mg/kg) include med T max values of 1 h for both ADC and total antibody (TA), whereas med T max values for free MMAE range from 65 to 89 h. At 1.8 mg/kg, mean t 1/2 values are 58 h, 92 h, and 95 h for the ADC, TA and MMAE, respectively. ADC exposure has been highest at 1.8 mg/kg, with mean C max and AUC last values of 31.8 μg/mL and 1297 μg*h/mL, respectively. Conclusions: BC3195 has a manageable safety profile, favorable PK characteristics and demonstrated preliminary antitumor activity in several types of heavily pretreated advanced solid malignancies. Based on shared safety data, enrolment in both BC3195-102 (US) and BC3195-101 (China), which is in dose expansion, is converging on the 2.1 mg/kg DL (NCT06548672). Clinical trial information: NCT06548672 .

Diagnostic accuracy of frozen sections for intraoperative detection of spread through air spaces in early-stage lung cancer: Systematic review and meta-analysis.

e20062 Background: Tumor spread through air spaces (STAS) is an independent predictor of recurrence and lung cancer–specific mortality in early-stage lung cancer. Intraoperative detection of STAS using frozen section analysis may aid surgical decision-making by guiding appropriate selection between lobectomy and sub-lobar resection. Methods: We systematically searched five databases from inception to October 2025 to identify PICO-concordant studies evaluating the diagnostic accuracy of intraoperative frozen section analysis for detecting STAS, using permanent paraffin sections as the reference standard. Pooled sensitivity, specificity, SROC curves, and diagnostic odds ratios were estimated using Bayesian bivariate hierarchical and random-effects models. Heterogeneity, sensitivity analyses, and publication bias were assessed in R (v2024.12.0+467) using the meta and mada packages. Results: Using a Bayesian bivariate hierarchical model, frozen section analysis demonstrated a pooled sensitivity of 0.66 (95% credible interval [CrI], 0.51–0.79) and specificity of 0.87 (95% CrI, 0.68–0.95), with a diagnostic odds ratio (DOR) of 12.74 (95% CrI, 1.86–23.63). Substantial heterogeneity was observed (I²E sensitivity: 0.82 [0.74–0.89]; I²E specificity: 0.72 [0.47–0.96]), with between-study variance estimates of 0.74 for logit sensitivity and 2.80 for logit specificity. In univariate analyses, pooled sensitivity was 0.60 (95% CI, 0.49–0.70; I² = 65.6%) and specificity was 0.87 (95% CI, 0.65–0.96; I² = 93.5%), yielding a DOR of 13.90 (95% CI, 5.95–32.49; I² = 88.6%). Heterogeneity remained stable on leave-one-out and subgroup analyses. Deeks’ funnel plot showed no evidence of publication bias (p = 0.62). Conclusions: Frozen section analysis demonstrates relatively high specificity but moderate sensitivity for STAS detection, making it more suitable as a rule-in rather than a rule-out test. Positive intraoperative findings may support escalation to lobectomy, whereas negative results should be interpreted with caution.

Race/ethnicity-stratified survival differences associated with psychotropic medication use in pancreatic cancer.

12072 Background: Pancreatic cancer is linked to poor survival and a high burden of neuropsychiatric symptoms. Psychotropic medications are used to manage these symptoms, yet racial/ethnic disparities in use have been reported. The association between psychotropic use and survival in pancreatic cancer across racial and ethnic groups remains unclear. We evaluated race/ethnicity–stratified differences in 2-year survival associated with psychotropic use among older adults with pancreatic cancer. Methods: Retrospective cohort study using SEER–Medicare data (2007–2019) including patients aged ≥65 years with incident pancreatic cancer and continuous Medicare Parts A, B, and D coverage. Psychotropic use was defined as ≥1 Part D claim for antipsychotics, antidepressants, or anxiolytics. Overall survival was assessed using restricted mean survival time (RMST) up to 730 days post-diagnosis. RMST differences between users and non-users were compared within race/ethnicity strata (non-Hispanic White = NHW, non-Hispanic Black = NHB, Hispanic, Other) Sidak-adjusted chi-square tests. Results: Among 81,535 patients, 33.8% received at least one psychotropic medication. Overall psychotropic use was associated with a modest increase in RMST (+8.3 days), driven by antidepressants (+10.7 days) and anxiolytics (+26.8 days), while antipsychotic use was associated with shorter RMST (−13.7 days). RMST gains varied by race/ethnicity, with larger increases among NHB (+17.1 days) and Hispanic patients (+16.4 days), smaller gains among NHW (+4.1 days), and no benefit among Other races (−3.6 days). Antipsychotic-associated RMST deficits were greatest among NHB patients (−34.4 days). Antidepressants were associated with longer RMST across all groups whereas anxiolytic benefits were not observed among Other races. Conclusions: In this cohort of older adults with pancreatic cancer, psychotropic medication use was associated with modestly longer survival overall, largely attributable to antidepressants and anxiolytics, while antipsychotic use was associated with shorter survival. Survival associations varied by race and ethnicity, with larger gains among NHB and Hispanic patients. These findings underscore the importance of equitable recognition and management of neuropsychiatric symptoms and support further research incorporating symptom severity and medication use. RMST difference (days) comparing psychotropic users vs non-users stratified by race/ethnicity. Overall Cohort(N=81,535) NHW(N=59,059) NHB(N=8,015) Hispanic(N=8,993) Other(N=5,468) Any psychotropic 8.3 (1.8) 4.1 (2.2) 17.1 (6.0) 16.4 (5.7) −3.6 (7.4) Antipsychotics -13.7 (3.7) −14.4 (4.4) −34.4 (11.3) 6.2 (11.9) −17.0 (14.47) Antidepressants 10.7 (2.0) 6.6 (2.4) 16.3 (6.8) 16.2 (6.3) 21.1 (8.70) Anxiolytics 26.8 (2.36) 23.5 (2.7) 44.1 (9.1) 34.2 (7.8) −2.4 (10.02) Bolded values are statistically significant.

Oncologic outcomes following biologic therapy for immune-related cutaneous adverse events.

12156 Background: Biologic agents are increasingly used to treat immune-related cutaneous adverse events (ircAEs). However, limited data exist regarding immune checkpoint inhibitor (ICI) rechallenge and ICI efficacy following biologic therapy for ircAE management. Methods: We conducted a retrospective cohort study of patients enrolled under U01AR077511-01 (PIs Leung, Kern, Lacouture) treated with ICIs who developed dermatologist-confirmed grade ≥2 ircAEs. Demographics, ircAE treatments, and dermatologic and oncologic outcomes were collected via chart review and compared using t-tests and chi-square tests. Results: We identified 159 patients who developed grade ≥2 ircAEs, including 80 treated with biologic agents. Mean age was 66.8 years; 40% were female, 79% White, and 78% had stage IV disease. The most common tumor types were kidney (20%), lung (16%), and melanoma (12%). Common ICI regimens included ICI monotherapy (46%), ICI–ICI combination (21%), and ICI+chemotherapy (19%). Pruritus (23%), maculopapular rash (21%), and eczema (19%) were the most common ircAEs. Most patients received topical steroids (88%), while systemic steroids were used sparsely (13%). Biologics were used in ~50% of patients; the most common agents were dupilumab (43%), omalizumab (33%), and ustekinumab (11%). Median biologic duration was 16 weeks, with 25% receiving therapy for &gt;40 weeks. ICI rechallenge occurred in 60% of biologic-treated versus 67% of non-biologic patients (p=0.35). Rechallenge rates were 67% vs 65% for grade 2 (p=0.85) and 44% vs 74% for grade 3 ircAEs (p=0.05) (biologic vs non-biologic, respectively). Antitumor outcomes were similar between biologics and non-biologic groups: 31% vs 28% achieved partial/complete response, 43% had stable disease, and 26% vs 29% had progressive disease, respectively. Conclusions: In this oncodermatology-managed cohort, ircAEs were primarily treated with topical corticosteroids and targeted biologics, with infrequent systemic steroid use. Biologic therapy enabled ICI rechallenge in most patients, and oncologic outcomes were comparable to those not receiving biologics. Overall, these findings support biologics as a steroid-sparing option for moderate-to-severe ircAEs that may allow continued immunotherapy without apparent loss of antitumor efficacy, warranting prospective validation. Clinical characteristics. Variable Overall n=159 No Biologics n=79 Biologics n=80 Age at ICI (mean) 66.8 64.3 69.4 Tumor Types Kidney/Lung/Melanoma (%) 20/16/12 22/17/9 18/15/15 Line of treatment 1L/2L/2+L (%) 52/25/23 49/27/24 54/24/22 ircAEs: Pruritus/MPR/Eczema/Others (%) 23/21/19/37 22/33/17/28 25/9/21/45 ircAE Grade 2/Grade 3 (%) 74/26 76/24 71/29 Dupilumab/Omalizumab/Ustekinumab/Others (%) 33/33/11/23 N/A 33/33/11/23 Systemic Steroids - Yes (%) 13 8 18 ICI Rechallenge - Yes (%) 64 67 60 Response CR-PR/SD/PD (%) 30/43/27 31/43/26 28/43/29

Outcomes of mortality and health care utilization in frail older patients with cancer receiving target therapies and/or immunotherapy.

1662 Background: ASCO &amp; NCCN guidelines recommend geriatric assessment for cancer patients aged 65+ to identify vulnerabilities missed on standard evaluations. Patients with G8 ≤14 (High risk) are potentially frail and at risk for chemotherapy toxicity, early mortality and ED visits/hospitalizations. However, there is currently limited evidence regarding the impact of a high-risk G8 score on outcomes among older frail patients receiving immunotherapy or targeted therapies. Methods: G8 screening was done at initial oncology consultation. Data was analyzed for individuals aged 65 and above referred between January 2021 and December 2024. Outcomes were measured 180 days after referral. A chi-square test assessed the relationship between demographic or outcome variables and G8 score. Multivariate regression and survival models predicted outcomes using age, sex, ethnicity, cancer type, and risk score. Results: This study included 1,671 patients receiving targeted therapy and/or immunotherapy. Participants ranged in age from 65 to 102 (median 75). Higher risk scores were linked to lower BMI (underweight: 92%, healthy: 74%, overweight/obese: 57%, p &lt; .0001), older age (p &lt; .0001), and female sex (73% vs 62%, p &lt; .0001). Ethnicity was not related to risk scores. High risk patients receiving target and/or immunotherapy had over 3x higher mortality rates at 180 days than low risk ones (p &lt;0.0001). They were also 1.4x as likely to have an ED Visit or hospitalization, 2x as likely to be referred to palliative care, and 5x as likely to be referred to hospice (p &lt; 0.0001). Multivariate analysis showed patients with upper GI and thoracic cancers were 1.4x more likely to be admitted and had over 2.7x mortality rate compared to those with breast cancer (p &lt; .0001 - 0.0188). A total of 515 patients underwent only immunotherapy. Outcome trends and the association between risk score and demographics were similar to the combined target therapy and/or immunotherapy study. Conclusions: A high-risk G8 score (≤14) is linked to higher mortality and more emergency visits or hospitalizations in older cancer patients receiving immunotherapy or targeted therapies. It is recommended that oncologists integrate geriatric assessment results into treatment decisions involving immunotherapy and targeted therapies. Outcomes of patients by risk score and treatment type 180 days after referral. Risk Score/Treatment Type Mortality ED Visits orHospitalizations Palliative Care Referral Hospice Referral High risk G8-Combined target/Immunotherapy 15.3% 51.1% 33.0% 12.1% Low risk G8 - Combined Target/Immunotherapy 3.7% 29.2% 14.8% 2.3% p-value &lt;0.0001 &lt;0.0001 &lt;0.0001 &lt;0.0001 High risk G8 - Immunotherapy alone 26.5% 61.5% 40.1% 22.3% Low risk G8 - Immunotherapy alone 8.7% 43.5% 19.6% 5.1% p-value &lt;0.0001 0.001 &lt;0.0001 &lt;0.0001

Mutational profile of colorectal cancer cells in patients with multiple primary cancers.

e15538 Background: Colorectal cancer (CRC) is one of the three most common malignancies and a frequent component of multiple primary cancers (MPCs). The molecular mechanisms driving the development of MPCs remain incompletely understood. This study aimed to investigate the mutational landscape of CRC occurring within the context of MPCs. Methods: The study included 450 patients with single primary CRC (sCRC) and 62 patients with synchronous or metachronous MPCs involving CRC. DNA was isolated from formalin-fixed, paraffin-embedded tumor tissues. All samples were analyzed for KRAS , NRAS , and BRAF mutations, as well as microsatellite instability (MSI) status. A subset of MPCs cases underwent targeted high-throughput next-generation sequencing (NGS). Bioinformatics tools were used for data analysis. Results: No significant differences in gender, age, or histological type were observed between the MPCs and sCRC groups. The frequency of the KRAS G12A mutation was significantly higher in the MPCs group (17.7%, n = 11) compared to the sCRC group (p &lt; 0.0001; OR = 15.96; 95% CI [5.66–44.98]). A relative predominance of MSI-high status was also found in the MPCs group (p &lt; 0.04; OR = 2.32; 95% CI [1.004–5.37]). Targeted NGS of CRC samples from the MPCs cohort revealed 109 genetic variants across 16 of the 32 genes analyzed. The most commonly mutated genes were TP53 , KRAS , PIK3CA , APC , and BRAF , predominantly involving missense and nonsense mutations. Conclusions: This study demonstrates that CRC arising as part of MPCs has a distinct molecular profile, characterized by a higher prevalence of specific KRAS mutations and MSI-high status. These findings provide a basis for further research into the molecular pathogenesis of MPCs, which may inform the development of improved treatment and surveillance strategies.

The effect of perioperative radiotherapy on prognosis in patients with operable rectal cancer who received neoadjuvant chemotherapy and underwent surgery.

e15681 Background: Total neoadjuvant therapy has emerged as a contemporary treatment strategy for operable rectal cancer, aiming to enhance systemic disease control and improve surgical outcomes. While neoadjuvant chemotherapy constitutes a key component of this approach, the incremental benefit of adding perioperative radiotherapy remains unclear, particularly in terms of long-term survival. Evaluating the prognostic impact of perioperative radiotherapy in patients receiving neoadjuvant chemotherapy may clarify its role in optimizing local control and survival. This study aimed to assess the effect of radiotherapy on cancer-specific mortality in patients with operable rectal cancer who received neoadjuvant chemotherapy. Methods: This retrospective cohort study analyzed data from the Surveillance, Epidemiology, and End Results (SEER) database to identify patients with operable rectal cancer diagnosed between 2000 and 2022 who received neoadjuvant chemotherapy followed by curative-intent surgery. Patients were grouped according to perioperative radiotherapy use. Demographic, clinicopathological, and treatment related variables were extracted. Overall and cancer-specific survival were assessed using Kaplan– Meier analysis, and independent prognostic factors were evaluated using multivariate Cox proportional hazards regression. Results: The study was analyzed using data from 6404 patients. The proportion of male patients was 62%. The stage distribution at diagnosis for the patients included in the study was stage 1 (9.7%), stage 2 (26.8%), and stage 3 (63.5%), respectively. All patients had undergone primary tumor surgery, and all had received neoadjuvant chemotherapy. 44.9% of patients had elevated CEA markers at diagnosis. 433 (6.8%) patients died during follow-up. The 1, 3, and 5-year survival rates were 98.4%, 90.6%, and 83.4%, respectively. Factors affecting survival were evaluated using multivariate analysis, and the results were as follows: age (p &lt; 0.001), gender (p = 0.028), race (p = 0.007), initial stage (p &lt; 0.001), radiotherapy (p = 0.011), and CEA level (p &lt; 0.001). Survival was better in patients who received radiotherapy (p: 0.011, HR: 1.68, 95% CI: 1.12-2.5). Conclusions: In this study, we evaluated the effect of radiotherapy on overall survival in patients with resectable rectal cancer. In stage 2 and stage 3 patients receiving neoadjuvant chemotherapy for resectable rectal cancer, radiotherapy improved overall survival. We found that the disease prognosis was worse in men, elderly patients, individuals of black race, and patients with high CEA levels at diagnosis.

Real-world outcomes of systemic therapy in patients with anaplastic thyroid carcinoma.

e18135 Background: Anaplastic thyroid carcinoma (ATC) is a rare and highly aggressive malignancy with limited treatment options and poor survival outcomes. Real-world data on systemic therapies, including targeted treatments and chemotherapy, remain limited. Methods: This retrospective analysis included 10 patients with ATC treated at a tertiary cancer center between 2019 and 2025. Five patients received dabrafenib/trametinib and five received chemotherapy as first-line systemic therapy (cisplatin–doxorubicin, n=3; paclitaxel–carboplatin, n=2). Clinical characteristics, treatment response, progression-free survival (PFS), and overall survival (OS) were evaluated using the Kaplan–Meier method. Results: The median age was 60 years (IQR: 54.7–67.7), and 50% of patients were male. At diagnosis, 10% had stage IVB disease and 90% had stage IVC disease. Primary tumor resection was performed in 60% of patients. The most common metastatic sites were lymph nodes (80%) and lungs (30%). BRAF mutations were identified in 50% of patients, and the median PD-L1 expression was 22.5% (IQR: 10.5–27.5) (Table 1). Objective responses were observed in three patients in the chemotherapy group and two in the dabrafenib/trametinib group. Disease control was achieved in four and five patients, respectively. The median follow-up duration was 11.9 months (IQR: 3.7–12.1). In both treatment groups, three patients died and four experienced disease progression. The median PFS in the overall cohort was 5.7 months (95% CI: 5.2–6.2). Median PFS was 5.1 months (95% CI: 3.0–7.1) with chemotherapy and 5.7 months (95% CI: 4.5–6.9) with dabrafenib/trametinib (p = 0.06). The median OS was 11.9 months (95% CI: 6.5–17.3) overall, 7.7 months (95% CI: 6.5–8.9) with dabrafenib/trametinib, and 12.6 months (95% CI: 0–26.0) with chemotherapy (p = 0.23). Conclusions: Systemic therapies provided limited but clinically relevant benefit in patients with anaplastic thyroid carcinoma. Nevertheless, survival outcomes remained poor, highlighting the need for improved therapeutic strategies for this aggressive disease. Baseline demographic and clinical characteristics of patients with anaplastic thyroid carcinoma. Variable Patients n=10 Age, median (IQR) 60 (54.7–67.7) Age ≥65 years 4 (40%) Female 5 (50%) Male 5 (50%) Stage IVB 1 (10%) Stage IVC 9 (90%) Primary tumor resection 6 (60%) Primary tumor radiotherapy 2 (20%) Palliative radiotherapy 9 (90%) Bone metastasis 3 (30%) Lymph node metastasis 8 (80%) Lung metastasis 4 (30%) Liver metastasis 1 (10%) Other metastasis 1 (10%) No driver mutation 5 (50%) BRAF mutation 5 (50%) PD-L1 expression, median (IQR) 22.5 (10.5–27.5) Dabrafenib/Trametinib 5 (50%) Chemotherapy 5 (50%) Progression 8 (80%) Death 6 (60%) Data are presented as n (%) or median (IQR). Abbreviations: ATC, anaplastic thyroid carcinoma; ChT, Chemotherapy; IQR, interquartile range.

Clinical impact of first-line platinum plus two-day etoposide combined with immunotherapy in extensive-stage small cell lung cancer: Retrospective monocentric study—E-twoposide.

e20161 Background: Standard first line treatment for extensive-stage small cell lung cancer typically includes carboplatin, etoposide over 3 days, and immunotherapy. In our center, a modified regimen using a two-day schedule for chemotherapy was implemented with the goal of simplifying treatment delivery while maintaining efficacy. This retrospective study imed to evlauate the clinical outcomes and safety of this approach. Methods: We included all patients with ES-SCLC treated between january 2021 and december 2024 with the following regim : carboplatin (AUC 5) on day 1, etoposide 150mg/m2 on days 1 and 2, combined with immunotherapy (eithe durvalumab or atezolizumab). Primary endpoints were progression free survival and overall survival. Secondary endpoints included treatement related toxicities. Results: A total of 87 patients were included. The median PFS was 4.8 months and the median OS was 11.3months. Grade 3 and 4 adverse events occured in 61% of patients principally haematologic disorders. Unexpected toxicities or treatment-related deaths were not observed. Conclusions: A modified two-day chemotherapy regimen combined with immunotherapy appears to offer comparable efficacy and acceptable safety to the standard approach. This modified regimen allowed the release of 268 chemotherapy treatment slots in our center and, pending prospective evaluation, may represent a feasible alternative to the standard schedule.

Hippocampus avoidance versus standard prophylactic cranial irradiation for small cell lung cancer: A systematic review and meta-analysis of randomized controlled trials.

e20151 Background: Prophylactic cranial irradiation (PCI) for limited stage (LS-SCLC) or extensive stage small cell lung cancer (ES-SCLC) reduces incidence of brain metastases, but causes neurocognitive function (NCF) decline. Hippocampus is critical for updating cognitive representations to reflect changing social and environmental context. We aim to compare the effects of hippocampus avoidance PCI (HA-PCI) versus standard PCI on neurocognition, incidence of brain metastasis, overall survival and toxicity, in patients with small cell lung cancer. Methods: We searched PubMed, Embase, and Cochrane database for randomized control trials (RCTs) comparing HA-PCI, defined as 5mm Hippocampal avoidance zone (HAZ) versus standard PCI in patients with small cell lung cancer without prior brain metastasis. The primary outcome was decline in NCF, measured by the Hopkins Verbal Learning Test- Revised (HVLT-R) and Free and Cued Selective Reminding Test (FCSRT). The secondary outcomes include incidence of brain metastasis, overall survival and toxicity. Statistical analysis was performed using Review Manager (version 5.4) (Cochrane Collaboration). Heterogeneity was assessed with I 2 statistics. The protocol is registered in PROSPERO (CRD420251250284). Results: We included 711 patients from three RCTs, including 355 (49.9%) patients of HA-PCI group. Patients received radiation of 25 Gy in 10 fractions, with mean dose of ≤ 8.5 Gy to the HAZ across trials. In LS-SCLC (n = 500), 245 received HA-PCI and 255 received PCI; in ES-SCLC (n = 211), 111 received HA-PCI and 100 received PCI. Pooled analysis of binary outcomes showed there is a non-significant trend toward reduced risk of NCF decline in HA-PCI compared to standard PCI. This was observed across both verbal learning (total recall) (RR 0.89; 95%CI 0.56 - 1.43; p = 0.64; I 2 = 58%) and delayed memory (delayed recall) (RR 0.62; 95%CI 0.22 - 1.75; p = 0.36; I 2 = 82%). Subgroup analysis between two different tests measuring verbal learning showed significant difference (p = 0.03). The cumulative incidence of brain metastasis at two years was not significantly reduced in HA-PCI group (RR 0.97; 95%CI 0.67 - 1.42; p = 0.89; I 2 = 0%). No significant effect on overall survival (HR 1.02; 95% CI 0.83 - 1.25; p = 0.87; I 2 = 0%). Subgroup analysis for stage (LS-SCLC vs. ES-SCLC) showed no significant difference (p = 0.20). Toxicity analysis showed HA-PCI significantly had lower incidence of skin and subcutaneous tissue disorders compared to standard PCI (RR 0.68; 95%CI 0.49 - 0.95; p = 0.02; I 2 = 0%). Conclusions: In conclusion, hippocampus avoidance PCI demonstrated comparable oncologic outcomes to standard prophylactic cranial irradiation, with a non-significant trend toward HA-PCI, suggesting it may reduce neurocognitive failure across different assessments, in patients with SCLC.

Real-world patterns and temporal trends of first-line immunotherapy use in metastatic NSCLC in Brazil according to PD-L1 expression.

e20631 Background: First-line (1L) treatment of metastatic NSCLC has evolved rapidly with the incorporation of immune checkpoint inhibitors (IO), administered either as monotherapy or combined with chemotherapy (CT). While PD-L1 expression is a key biomarker guiding treatment selection, real-world data describing temporal trends and PD-L1–driven decisions among patients receiving IO in Latin America remain scarce. Methods: This retrospective, observational, multicenter study included patients aged ≥18 years with unresectable or metastatic NSCLC treated with 1L systemic therapy between January 2021 and December 2023 at seven Brazilian cancer centers. Patients with non-epithelial histology and neuroendocrine tumors were excluded. Clinical, pathological, and biomarker data were collected using standardized eCRFs. The present analysis focused on patients receiving 1L immunotherapy with or without chemotherapy. Descriptive statistics were used. Associations were assessed using Fisher’s exact or Student’s t-test, as appropriate. OS was estimated using the Kaplan–Meier method and explored using univariable Cox regression. Analyses were conducted using R (v4.4.2). Results: Among 500 included patients, median age was 69.5 years; 61% were current/former smokers, 61% had &lt; 2 comorbidities, and 80% had ECOG 0–1. Adenocarcinoma was the predominant histology (80%), and 82% had metastatic disease at diagnosis. PD-L1 expression was &lt; 1% in 30.8%, 1–49% in 29.4%, and ≥50% in 20.8%. Overall, 245 patients (49.0%) received IO-based 1L therapy. CT+IO was the most frequently used regimen (85.0%), predominantly platinum-based chemotherapy plus pembrolizumab, whereas IO monotherapy accounted for 15.0% of cases. Treatment choice was significantly associated with PD-L1 status (p &lt; 0.001): 56.8% of patients receiving IO monotherapy had PD-L1 ≥50%. Dual IO-based regimens were used in a minority of patients, mainly among those with PD-L1 &lt; 1%. Use of intensified IO-based combinations increased over time, from 1.4% in 2021 to 13.2% in 2023. PD-L1 expression showed a trend toward improved OS with increasing expression levels. Conclusions: In this real-world Brazilian cohort, PD-L1 expression played a central role in guiding first-line immunotherapy selection for metastatic NSCLC, supporting its continued clinical relevance in routine practice. However, the heterogeneity of outcomes across PD-L1 subgroups underscores the need for additional predictive biomarkers to further refine patient selection and optimize immunotherapy-based treatment strategies.

Clinical characteristics, management, and outcomes of pediatric non-infectious uveitis: A multicenter study in Saudi Arabia

Background Pediatric non-infectious uveitis is a challenging condition with significant risks for long-term ocular complications and visual impairment. Limited regional data on its clinical characteristics and outcomes in Saudi Arabia are available. Objective This study aimed to describe the clinical features, management strategies, and outcomes of pediatric non-infectious uveitis in two major medical centers in Saudi Arabia. Methods A retrospective observational study was conducted, including 36 pediatric patients diagnosed with non-infectious uveitis from January 2017 to December 2023. Data were collected on demographic characteristics, clinical presentation, laboratory findings, treatment modalities, and follow-up outcomes at 3, 6, 12, and 24 months. Descriptive and inferential statistics were used for analysis. Results Among the 36 patients, 66.67% were female, and the mean age at diagnosis was 8.99 ± 4.17 years. The most common etiology was juvenile idiopathic arthritis (52.8%), followed by idiopathic uveitis (25%) and Vogt-Koyanagi-Harada disease (19.4%). Bilateral involvement was present in 55.6% of cases, with anterior uveitis being the predominant type (75%). Antinuclear antibody (ANA) positivity was observed in 69.44% of patients. The most frequently used treatments at diagnosis included prednisolone acetate 1% (91.67%) and methotrexate (50%). Over the 2-year follow-up, 86.11% of patients achieved remission, although complications such as synechiae (13.89%), cataracts (8.3%), and band keratopathy (5.56%) were observed. Visual acuity outcomes improved in most cases, although delayed presentation and non-compliance posed challenges. Conclusion Pediatric non-infectious uveitis in Saudi Arabia mirrors global patterns, with JIA being the leading cause. Early diagnosis and biologic therapies have improved remission rates and reduced complications. Future efforts should focus on enhancing screening, patient adherence, and access to advanced therapies to optimize outcomes for affected children.

Interfacial Charge‐Regulated Microenvironments Enabled by Ionic Organic Cages for Boosting Electrocatalytic Nitrate Reduction to Ammonia

ABSTRACT Ammonia (NH 3 ) is essential for agriculture and industry, yet the Haber–Bosch process is energy‐intensive and carbon‐emissive. Electrochemical nitrate reduction reaction (NO 3 RR) offers a sustainable alternative by coupling NH 3 synthesis with water remediation. However, challenges such as weak NO 3 − adsorption, competing hydrogen evolution, and suboptimal catalyst microenvironments hinder performance. Here, we report a family of electrocatalysts, Pd⊂QA‐Cage x + ( x = 24, 12, 6), constructed by encapsulating Pd clusters within quaternized organic cages. These discrete hosts enable uniform metal cluster confinement and precise control over the interfacial microenvironment. Increasing cage charge density enriches interfacial NO 3 − concentration, upshifts Pd d ‐band center, and enhances *NO 3 activation. Simultaneously, potential‐driven electron transfer from the counterion (Cl − ) to –NH 2 + – generates stable radicals in the cage skeleton, which mediate water activation to form hydrogen radicals (H•) that spill over to Pd sites, accelerating intermediate hydrogenation. The optimized Pd⊂QA‐Cage 24+ delivers a Faradaic efficiency of 95.44% and an NH 3 yield of 25.70 mg h − 1 mg cat − 1 in neutral electrolytes, outperforming its lower‐charge analogs. Moreover, it enables &gt; 99.4% nitrate removal from eutrophic seawater, reducing NO 3 − concentrations below potable water standards. This work introduces ionic cages as programmable interfacial modifiers, offering a supramolecular strategy to regulate electrochemical microenvironments and boost electrocatalytic NO 3 RR performance.

Spectroscopic investigation of Cd²⁺ detection using an optimized multilayer CdS/CS₂/2D material-based SPR sensor