Browse Articles

Real-world post-APT trial adoption of de-escalated systemic therapy and outcomes in small HER2-positive breast cancer: An NCDB analysis.

539 Background: The APT trial shifted adjuvant management of small HER2-positive breast cancer towards paclitaxel-trastuzumab, yet real-world uptake and outcomes of de-escalated single-agent chemotherapy (SC) plus anti-HER2 therapy (H) vs multi-agent chemotherapy (MC) plus H remain uncertain. Methods: Using NCDB (2013-2022), we identified patients with invasive HER2-positive pT1a-pT1c, pN0/N1mi, M0 disease treated with surgery without neoadjuvant therapy. We compared treatment patterns pre-APT (2013-2014) vs post-APT (2016-2022), excluding 2015 as a washout. Regimens were grouped as local therapy only, H only, chemo only, SC + H, or MC + H. Predictors of SC + H were assessed with multivariable logistic regression in post-APT chemo + H recipients. OS was evaluated using time-varying Cox models (time zero surgery; treatment exposure starting at recorded systemic therapy initiation), adjusted for demographic, tumor, and facility factors. In the overall cohort, each regimen (H only, chemo only, SC+H, and MC+H) was compared with local therapy only. For pT1a tumors, comparisons were limited to H only, chemo only, and any chemo + H vs local therapy. To evaluate whether de-escalation was associated with similar OS, SC + H vs MC + H was compared in separate Cox models restricted to chemo + H recipients in pT1b and pT1c. Results: Among 56,455 patients, SC + H use increased from 12.5% pre-APT to 40.3% post-APT, while MC + H decreased from 46.6% to 24.8% ( p < 0.001). In the post-APT era among chemo + H recipients (N = 24,867), SC + H use increased with age (per 10-year OR 1.32, 95% CI 1.27-1.36) and hormone receptor-positive (HR-positive) status (OR 1.37, 95% CI 1.27-1.49), and less common with pT1c (OR 0.47, 95% CI 0.43-0.51) and N1mi (OR 0.21, 95% CI 0.17-0.24) tumors. In OS analyses of the entire cohort with available systemic start dates (N = 51,078; deaths = 3,246), SC + H (HR 0.62, 95% CI 0.57-0.67) and MC + H (HR 0.63, 95% CI 0.58-0.68) were associated with improved OS vs local therapy only. Additional independent predictors of mortality included Black race, older age, and higher tumor burden (T1c and N1mi), while HR-positive was linked to better OS. In pT1a cohort (N = 10,212; deaths = 461), any chemo + H was associated with improved OS vs local therapy (HR 0.83, 95% CI 0.70-1.00, p = 0.049), while H only (HR 0.85, 95% CI 0.51-1.42) and chemo only (HR 1.14, 95% CI 0.74-1.74) were not. Among chemo + H recipients, OS was similar for SC + H vs MC + H in pT1b (HR 0.96, 95% CI 0.80-1.16) and pT1c (HR 1.09, 95% CI 0.97-1.24) cohorts. Conclusions: Since APT, real-world care has shifted towards de-escalated SC + H regimens. Among treated pT1b and pT1c patients, OS was similar with SC vs MC backbones, supporting the feasibility of de-escalation in selected patients. In pT1a disease, the OS association for chemo + H was marginal ( p = 0.049) and should be interpreted cautiously given non-random treatment selection and low event rates.

RATIONALE-315: Post hoc analysis of event-free survival by surgically relevant subgroups treated with perioperative tislelizumab and neoadjuvant chemotherapy vs neoadjuvant chemotherapy.

8059 Background: RATIONALE-315 (NCT04379635) compared the efficacy and safety of perioperative tislelizumab (TIS) or placebo (PBO) + neoadjuvant chemotherapy (CT) in patients (pts) with resectable NSCLC. This post hoc analysis reports correlation of event-free survival (EFS) to key surgical outcomes. Methods: Pts with resectable stage II-IIIA NSCLC (N=453) were randomized 1:1 to 3-4 cycles of TIS 200 mg or PBO Q3W with neoadjuvant CT, followed by surgery and ≤8 cycles of adjuvant TIS 400 mg or PBO Q6W. Primary and key secondary endpoints were reported previously. Exploratory endpoints of surgical outcomes are presented here. Results: As of March 7, 2025, 190/226 pts in the TIS arm and 173/227 pts in the PBO arm underwent definitive surgery. EFS benefit with TIS vs PBO was observed in all surgically relevant subgroups (HR: 0.62; 95% CI: 0.44-0.88). Although R0 resection rates were similar between treatment arms, TIS showed greater EFS benefit vs PBO (HR: 0.62; 95% CI: 0.43-0.90). A similar trend was observed in R1/R2 pts (HR: 0.75; 95% CI: 0.19-3.05); however, data should be interpreted with caution due to small pt numbers. Pts in the TIS arm who underwent open and minimally invasive surgery (n=179) achieved improved EFS benefit compared with those in the PBO arm (n=157), regardless of disease stage and surgery type (Table). In pts who underwent minimally invasive and open surgery, respectively, grade ≥3 treatment-emergent adverse events occurred in 77.2% and 78.8% of pts in the TIS arm and 71.3% and 81.7% in the PBO arm. In pts who underwent minimally invasive surgery in the TIS arm, grade ≥3 immune mediated adverse events were reported in 11.4% of all pts (13/114), 10.4% of pts in stage II (5/48), and 12.3% in stage IIIa (8/65). Conclusions: Perioperative TIS + neoadjuvant CT improved EFS in pts with resectable NSCLC across all surgically relevant subgroups regardless of disease stage or surgery type. These results further support TIS + CT as an efficacious and safe treatment option that may reduce the burden of invasive surgical intervention. Clinical trial information: NCT04379635 . EFS rate, % (95% CI) 12 mo 24 mo 48 mo Approach to surgery, NSCLC stage TIS PBO TIS PBO TIS PBO Minimally invasive  Overall 89.7 (82.2-94.2) 79.0 (78.0-86.6) 81.0 (72.1-87.3) 63.8 (51.8-73.6) 74.3 (64.0-82.1) 55.4 (42.0-67.0)  Stage II 90.9 (82.8-99.8) 85.0 (73.7-98.0) 83.6 (73.1-95.5) 69.8 (55.8-87.4) 77.0 (64.6-91.8) 66.5 (52.1-84.8)  Stage IIIa 88.7 (77.8-94.5) 73.1 (56.7-84.1) 78.9 (66.5-87.2) 58.0 (41.3-71.4) 72.4 (58.6-82.3) 46.7 (29.0-62.6) Open  Overall 78.5 (65.9-86.9) 70.9 (57.8-80.6) 60.2 (46.7-71.2) 47.8 (34.9-59.6) 54.1 (40.4-66.0) 31.1 (17.3-45.8)  Stage II 85.7 (72.0-100) 80.0 (64.3-99.6) 76.2 (60.0-96.8) 55.0 (37.0-81.8) 71.4 (54.5-93.6) NE (NE-NE)  Stage IIIa 74.1 (57.2-85.2) 66.4 (49.9-78.6) 50.3 (33.7-64.8) 44.3 (28.9-58.6) NE (NE, NE) 28.7 (13.9-45.5) NE, not evaluable.

Allogeneic CD19-targeted CAR-T therapy (BRL-301) for relapsed or refractory B-cell acute lymphoblastic leukemia (r/r B-ALL).

e14518 Background: Despite advances in treatment, outcomes for adults with relapsed or refractory B-cell acute lymphoblastic leukemia (r/r B-ALL) remain poor, with conventional chemotherapy achieving complete remission in only 18–45% of patients. Allogeneic CAR-T cells offer an "off-the-shelf" alternative but require genome editing to mitigate host rejection and graft-versus-host disease (GvHD). This study evaluates the safety and efficacy of BRL-301, a healthy donor-derived, multiplex genome-edited allogeneic CD19-targeted CAR-T product, in patients with r/r B-ALL. Methods: In this investigator-initiated trial (NCT05381181), patients with r/r B-ALL received lymphodepletion with etoposide, cyclophosphamide, and fludarabine followed by BRL-301 infusion. Safety and response assessments were conducted per protocol. Results: Five patients (median age 16 years, range 10–45) received BRL-301. All patients achieved an objective response, with a 100% complete response rate. Robust CAR-T expansion was observed in all subjects, peaking between days 7–18 post-infusion. Grade 3/4 adverse events included cytopenias attributable to lymphodepletion. All patients experienced mild (grade 1/2) cytokine release syndrome; 4 patients received tocilizumab and steroids. No immune effector cell-associated neurotoxicity syndrome (ICANS) or GvHD was observed. Conclusions: BRL-301 demonstrated promising efficacy and a manageable safety profile in patients with r/r B-ALL, with no evidence of GvHD or severe neurotoxicity. These results support further development of allogeneic CAR-T therapy as a viable treatment option for r/r B-ALL. Clinical trial information: NCT05381181 .

A multi-omic analysis of EOCRC: Divergent methylation and gene expression signatures in young patients.

3582 Background: The incidence of early-onset colorectal cancer (EOCRC; diagnosis < 50 years) is rising at an alarming rate. EOCRC often exhibits distinct clinical features compared to late-onset colorectal cancer (LOCRC), yet the underlying mechanisms remain poorly understood. This study aimed to characterize a cohort of EOCRC patients by integrating DNA methylation, gene expression, and metabolomic profiles to identify age-specific molecular drivers. Methods: We performed an integrated multi-omic analysis on a cohort of 42 patients, comprising 16 EOCRC and 26 LOCRC cases that were collected from the Total Cancer Care at the Ohio State University. For each patient, fresh-frozen tumor tissue and paired adjacent normal tissue were analyzed using reduced representation bisulfite sequencing (RRBS). Parallel transcriptomic profiling was conducted by RNA-seq on all tumor samples. Additionally, systemic metabolic signatures were captured from plasma using liquid chromatography-mass spectrometry (LC-MS). Functional integration of differentially methylated regions (DMRs), gene expression signatures, and metabolomic profiles was performed using Ingenuity Pathway Analysis (IPA) to identify enriched canonical pathways. Results: Integrative analysis revealed a divergent molecular fingerprint in EOCRC compared to LOCRC. At the epigenomic and transcriptomic levels, EOCRC tumors demonstrated significant enrichment in neurotransmitter-related pathways, such as CREB signaling in neurons and ion channel transport, alongside a pronounced activation of G-protein coupled receptor (GPCR) signaling. Furthermore, we identified a distinct immune-related signature characterized by the activation of phagosome formation and S100 family signaling pathways. These intracellular alterations were mirrored by a unique systemic metabolic profile involving the G alpha signaling pathway and the transport of vitamins, nucleosides, bile salts, and amine compounds. In addition, we identified a multi-omic signature of 11 genes that exhibit both differential gene expression between EOCRC and LOCRC tumors and significant tumor-specific methylation drift relative to adjacent normal tissue. Notably, this signature is enriched with established epigenetic clock/aging markers, including LEP , PLA2G4F , CYP2E1 , GCM2 , ZNF418 , and MINAR1 , making them ideal candidates for early detection by liquid biopsies or risk-stratification tools for EOCRC. Conclusions: Our findings demonstrate that EOCRC is a biologically distinct entity driven by specific epigenetic and immune dysregulation. The simultaneous enrichment of neurotransmitter pathways and GPCR signaling suggests that EOCRC development may be uniquely influenced by neuro-epithelial interactions. The 11-gene signature enriched with epigenetic aging markers may serve as screening or surveillance tools for EOCRC patients.

Clinicopathological characteristics of patients with minimal residual disease in stage II–III colon cancer: Interim results from the observational cohort of CLAUDIA study.

3635 Background: Circulating tumor DNA (ctDNA) monitoring for minimal residual disease (MRD) has emerged as a key prognostic biomarker in resected colon cancer. The CLAUDIA study (KCSG CO22-12, NCT05534087) is a prospective, multicenter study evaluating ctDNA-guided adjuvant therapy. It includes an observational screening cohort (Part 1) and a randomized interventional trial for MRD (+) patients (Part 2). Here, we report the baseline characteristics and MRD status of the Part 1 cohort and the clinical outcomes for patients who did not participate in Part 2. Methods: In Part 1, stage II or III colon cancer patients who received curative resection scheduled for adjuvant oxaliplatin-based chemotherapy (FOLFOX or CAPOX) are enrolled (N= approximately 1,200). Postoperative plasma samples collected after surgery, before starting adjuvant chemotherapy, are analyzed using a tumor-informed ctDNA assay that tracks up to 100 patient-specific mutations (IMBdx). Patients identified as MRD (+) are screened for a Part 2 randomized phase III trial (N=236) comparing mFOLFIRINOX to standard care. MRD (-) patients are managed at the investigator’s discretion. Results: As of November 2025, a total of 809 patients were enrolled. Postoperative ctDNA was positive in 228 patients (28.2%). MRD (+) rate was significantly higher in patients with T4 tumors (40.5% vs. 22.8% in T1–3 tumors, p<0.0001), N2 disease (38.8% vs. 25.4% in N0–1, p=0.0007), and elevated postoperative CEA (>5 ng/mL) (42.2% vs. 26.8% in normal, p=0.013). Accordingly, MRD (+) was enriched in high-risk stage III disease (T4 or N2) (40.3% vs. 21.5% in low-risk stage III and stage II, p<0.0001). However, MRD (+) rates did not differ significantly by histology, tumor location, or MSI status. MRD positivity was not associated with the mutational status of the frequently altered genes in colon cancer (APC, TP53, KRAS, BRAF, ERBB2, SMAD4). We analyzed outcomes in 673 patients who did not participate in the Part 2 randomized study [92 MRD (+) and 581 MRD (-)]. In the multivariate analysis of recurrence-free survival adjusting for clinicopathologic covariates, MRD (+) was the strongest independent predictor of poor outcome (adjusted HR 5.81; 95% CI 2.65–12.74; p<0.0001). Conclusions: Postoperative ctDNA status serves as a robust prognostic biomarker in stage II-III colon cancer, correlating with advanced tumor burden. MRD (+) patients who receive standard-of-care management face a significantly increased risk of recurrence. These findings validate the utility of the ctDNA assay used and support the rationale for the ongoing CLAUDIA Part 2 trial, which investigates treatment intensification for MRD (+) patients. Clinical trial information: NCT05534087 .

Integrin α _v β ₃ -targeted radionuclide therapy with ¹⁷⁷ Lu-AB-3PRGD ₂ in multiple advanced metastatic solid tumors: A prospective, single-arm, single-center, investigator-initiated clinical trial.

3009 Background: Tumor angiogenesis drives progression and metastasis in solid malignancies. Integrin α v β 3 is selectively overexpressed on multiple tumor cells and neovasculature with limited normal tissue expression, offering a promising therapeutic target. Our previous dose-escalation study investigated the safety and maximum tolerated dose of the integrin α v β 3 -targeted radiopharmaceutical ¹⁷⁷Lu-AB-3PRGD 2 . Building on this foundation, the current study aims to evaluate its therapeutic efficacy in patients with various advanced metastatic solid tumors. Methods: In this prospective, single-arm, single-center investigator-initiated clinical trial, eligible patients had histologically confirmed advanced metastatic solid tumors with documented progression after exhaustion of standard systemic therapies. Tumor integrin α v β 3 expression was confirmed by 68 Ga-3PRGD 2 PET/CT imaging. Patients received up to four cycles of 177 Lu-AB-3PRGD 2 at 3.7 GBq per cycle. The primary endpoint was ORR by RECIST 1.1. The secondary endpoints included DCR, PFS, OS, and safety. The sample size was calculated based on the primary endpoint of ORR. Assuming a null ORR of 10% and an alternative ORR of 30%, a one-sided binomial test with a significance level (α) of 0.05 and 80% power required approximately 20 evaluable patients. Results: From December 2023 to December 2025, 20 patients were enrolled. Of these, 5 received three treatment cycles and 5 received four cycles. The median age was 62 years (range 38–75) and 30% were female. Tumor types included radioiodine-refractory thyroid cancer (20%), breast cancer (15%), lung cancer (10%), cholangiocarcinoma (10%), renal cancer (10%), and others. At baseline, 65% of patients had ECOG performance status ≥2. Among 13 patients received ≥ 2 cycles of treatment, the ORR was 23% (3/13) and DCR was 92% (12/13), including 3 PR and 9 SD. With a median follow-up of 11.9 months, median PFS was 7.3 months and median OS was 18.5 months. Patients achieving disease control had significantly longer PFS and OS compared to those with progressive disease ( P < 0.001). Dosimetry analysis, available for 18 patients (90%), showed a mean tumor absorbed dose of 6.8 ± 5.4 Gy/GBq. Grade 3/4 treatment-related adverse events occurred in 20% of patients (4/20), primarily hematologic toxicities including thrombocytopenia (n = 4), leukopenia (n = 2), and anemia (n = 2). Conclusions: Integrin α v β 3 -targeted radionuclide therapy with ¹⁷⁷Lu-AB-3PRGD 2 demonstrated promising efficacy in disease control and tumor response, and it was generally well tolerated in patients with advanced metastatic solid tumors. These findings justify further investigation in prospective, multicenter, randomized clinical trials. Clinical trial information: NCT06375564 .

Evaluation of dietary habits and lifestyle in patients with bone sarcoma: Pilot study results of the Italian Metabol Sarc study (NCT04735289).

e23503 Background: Dietary behavior, lifestyle, and metabolic alterations such as obesity and insulin resistance are well established contributors to various cancers, with diet alone implicated in up to 40% of all cancers (Steck SE et al., 2020). In pediatric populations, maternal obesity and elevated birth weight, factors known to be influenced by dietary habits, are associated with increased risk of acute lymphoblastic leukemia and other malignancies (Stacy SL,2019). While the connections between diet, lifestyle, metabolic alterations (like obesity and insulin resistance), and cancer prognosis are well-recognized for many tumors, these relationships have not been thoroughly studied in bone sarcoma patients. We report here the results of a pilot cohort in Metabol Sarc protocol (NCT 04735289), a case-control study, conceived to investigate dietary, lifestyle, metabolomic, microbiota, and immune factors in patients with primary bone sarcoma. Methods: Participants aged ≥12 years with newly diagnosed primary bone sarcoma (osteosarcoma, Ewing sarcoma, spindle cell sarcoma, or dedifferentiated chondrosarcoma) were enrolled from multiple centers primarily the Rizzoli Institute, beginning March 2021. Controls were matched to cases by sex and age (±1 year for ages <21 years; ±2 years for ages ≥21 years). All participants completed the validated EPIC dietary questionnaire and lifestyle questionnaire (physical activity, education, electromagnetic exposure). Biological samples included fasting blood for routine laboratory tests and lymphocyte subpopulation phenotyping (CD3, CD4, CD8, NK cells). Results: The complete case pilot analysis included 73 patients (44 osteosarcoma, 29 Ewing sarcoma) and 139 matched controls (median age 23 years). After conditional logistic regression adjusted for weight, sex, and energy intake, linoleic acid intake was positively associated with bone sarcoma risk across all subtypes. Ewing sarcoma specifically showed stronger associations with animal-derived nutrients (animal fat, animal protein, total polyunsaturated fat). Conversely, body composition markers (Body Mass Index, lean mass, fat mass) showed no significant association with bone sarcoma risk. Immunological analysis revealed no distinctive serum markers for overall bone sarcoma; however, elevated CD4/CD8 ratio was positively associated with Ewing sarcoma. Controls had significantly higher educational attainment than cases. Conclusions: These preliminary findings support continued enrollment to achieve the planned sample size of 270 cases and matched controls. Currently, 133 patients and their matched controls have been enrolled. Results suggest potentially biologically plausible directional relationships that might be of interest, including associations related to dietary lipid composition.

Predicting 12-month overall survival from response rate and 6-month progression-free survival in oncology clinical trials: An embedding-based machine learning approach.

e13667 Background: Overall Survival (OS) remains the regulatory gold standard endpoint, but early trial decisions depend on Objective Response Rate (ORR) and intermediate Progression-Free Survival (PFS) to accelerate development timelines. Traditional endpoint surrogacy analyses demonstrate variable correlations across tumor types, stages, and treatment modalities. However, machine learning (ML)-based prediction of OS from early endpoints across heterogeneous trials remains limited. We developed an ML framework incorporating ORR, 6-month PFS rate, and LLM-based clinical and treatment embeddings to predict 12-month OS rate in a comprehensive cross-tumor clinical trials dataset. Methods: Data were extracted from the LARVOL CLIN outcomes database (2004–2023), comprising 1,029 Phase I–III trials (1,520 experimental and control arms) reporting ORR, 6-month PFS rate, and 12-month OS rate. To account for cross-trial heterogeneity, key population descriptors (tumor type, stage, setting, prior lines of therapy, biomarker status) were embedded separately to preserve granularity, while treatment details (regimen and dose/schedule) were embedded into a single representation. Embeddings from OpenAI text-embedding-3-large were used and reduced to 30 principal components (PCs) via Principal Component Analysis (PCA) (retaining 85% variance). ML models evaluated included XGBoost, LightGBM (LGBM), elastic net, and Random Forest (RF), with hyperparameters optimized using Optuna. Trial-grouped five-fold CV was used to prevent data leakage. Performance metrics included Coefficient of Determination (R²), Root Mean Squared Error (RMSE) and Mean Absolute Error (MAE) on a logit scale. Shapley Additive Explanations (SHAP) analysis was used to quantify relative feature contributions. Results: XGBoost achieved CV R² = 0.731 for 12-month OS rate prediction, outperforming RF CV R² = 0.498 (Table 1). SHAP analysis identified 6-month PFS rate (34.1%) and tumor type (24.2%) as dominant predictors, followed by arm description embeddings (9.5%) and stage (6.9%); ORR demonstrated a smaller relative contribution of 3.9%. Limitations include the modest dataset size and uncertain generalizability to rare tumor subtypes. Conclusions: ML models integrating early endpoints with LLM-based clinical and regimen embeddings achieved robust cross-tumor prediction of 12-month OS rate, supporting trial prioritization and OS hypothesis generation. SHAP analysis confirmed that 6-month PFS rate and tumor type were the dominant predictors. Models performance for 12-month OS prediction (logit scale). Model  R²  RMSE  MAE  XGBoost  0.731  0.465  0.35  LGBM  0.716  0.510  0.35  ElasticNet  0.556  0.769  0.42  Random Forest  0.498  0.817  0.44  Coefficient of Determination (R²), Root Mean Squared Error (RMSE) and Mean Absolute Error (MAE).

Taxane and platinum combination as a predictor of pathologic complete response in I-SPY2 by gene expression breast cancer signatures.

608 Background: Carboplatin is part of NCCN-preferred neoadjuvant chemotherapy (NAC) for stage II-III triple negative (TN) early-stage breast cancer (eBC) as addition to taxane-containing standard-of-care, and significantly improves pathologic complete response (pCR) rates in multiple trials. In hormone receptor (HR)+/HER2− disease, platinum addition has been explored in investigational settings but is not standard. In I-SPY2 (NCT01042379), high-risk eBC pts were randomized to standard taxane-anthracycline (T-AC) with or without investigational agents. One arm evaluated carboplatin plus the PARP inhibitor veliparib added to T-AC (VC arm; 32 HR+/HER2- and 39 TN pts, n = 71). Two gene signatures, a 205-gene Platin Drug Response Predictor (Platin-DRP) and a 113-gene taxane response predictor, have been validated for association with response to platinum agents and taxane-based regimens, respectively. This study evaluated their combined association with pCR in the I-SPY2 VC arm and their potential to inform platinum benefit in taxane-based NAC. Methods: Agilent gene expression data (GSE194040) from 987 high-risk eBC tumors were analyzed, focusing on 71 VC-arm pts and 179 HER2- T-AC pts. Samples were scored using each gene signature on a percentile scale (0–100). Associations between a 50-point increase in score and pCR were assessed using logistic regression with one-sided tests and 90% confidence interval (CI) lower bound (LB), unless otherwise specified. Results: The pCR rate in the VC arm was 38% (27/71), compared with 17.3% (31/179) in the control arm. In the VC arm, both the Platin-DRP (OR = 3.4, p = 0.016, 90% CI LB = 1.36) and the taxane predictor (OR = 3.88, p = 0.01, 90% CI LB = 1.54) were associated with pCR after adjustment for HR status and retained independent predictive value after adjustment for MammaPrint risk. The platinum and taxane scores were moderately correlated (r = 0.53). In a bivariable model, inclusion of the Platin-DRP trended toward improved fit beyond the taxane score alone (two-sided (2s) p = 0.082). Dichotomization at 50 showed highest pCR in double-high pts (55%, 16/29), intermediate rates in discordant pts (33%, 7/21), and lowest rates in double-low pts (19%, 4/21). Quartile stratification further separated outcomes, with 78% pCR (7/9) in the high-high quartile and 0% (0/8) in the low-low quartile.The taxane score showed no evidence of arm-specific effects (control vs VC; 2s p = 0.97), whereas the Platin-DRP showed directionally stronger associations in the VC arm (2s p = 0.12). Conclusions: Taxane and platinum gene expression signatures showed complementary associations with pCR in the I-SPY2 veliparib-carboplatin arm. Joint modeling and stratification identified subgroups with distinct responses, supporting the potential utility of combining drug-specific biomarkers to refine patient selection for platinum addition in taxane-based NAC.

Efficacy and safety of pralsetinib as first-line treatment of <i>RET</i> fusion–positive advanced or metastatic non–small cell lung cancer (NSCLC): The phase 3 AcceleRET-Lung study.

8504 Background: Pralsetinib, an oral tyrosine kinase inhibitor, selectively and potently targets oncogenic RET fusion and mutation proteins. Pralsetinib is FDA approved to treat adults with metastatic RET -altered NSCLC. We present efficacy and safety of pralsetinib vs standard of care (SOC) in first-line RET fusion-positive NSCLC from a randomized phase 3, open-label study, AcceleRET-Lung (NCT04222972). Methods: AcceleRET-Lung was conducted at 74 sites in 22 countries. Adults with RET fusion-positive advanced or metastatic NSCLC received pralsetinib 400 mg/d or platinum-based SOC therapy. Crossover to pralsetinib was optional upon progression. The primary end point was progression-free survival (PFS) per RECIST v1.1. Secondary end points included overall response rate (ORR), overall survival (OS), duration of response (DOR), and safety. Efficacy was evaluated in randomized patients (intent-to-treat population [ITT]). Safety was assessed in patients receiving ≥1 dose of study drug. Results: 223 ITT patients were randomized to pralsetinib (n=110) or SOC (n=113). Pralsetinib and SOC groups had similar baseline characteristics (median age: 62 and 63 y, respectively; female: 48% and 57%; median lesions: both 4; brain metastases: 15% and 16%). The study was terminated early per sponsor decision on January 27, 2025. ITT patients in the pralsetinib group had significantly greater median PFS vs SOC (18.7 vs 9.0 mo; P =0.003), ORR (65.5% vs 41.6%; P &lt;0.001), and median DOR (20.6 vs 9.7 mo; P =0.004; Table). Safety was generally consistent with the known pralsetinib profile except for a higher rate of infection in the pralsetinib group vs SOC (71.3% vs 51.9%), including pneumonia (19.4% vs 5.8%), urinary tract infections (17.6% vs 7.7%), and opportunistic infections (9.3% vs 1.0%). There were 32 (30.0%) and 26 (25.0%) deaths in the pralsetinib and SOC groups, respectively, with 8 (7.4%) and 0 due to infection. Common grade ≥3 TRAEs in the pralsetinib vs SOC groups were hypertension (11.1% vs 0), neutropenia (10.2% vs 8.7%), anemia (8.3% vs 10.6%), and decreased neutrophil count (7.4% vs 4.8%). Conclusions: In a Phase 3 study, pralsetinib met the primary PFS end point and had a significantly greater and more durable ORR vs SOC, confirming the clinical utility of pralsetinib in RET fusion-positive NSCLC. Monitoring for infections with pralsetinib is warranted. Clinical trial information: (1) NCT04222972 ; (2) 2023-505035-12-00; (3) 2019-002463-10. Efficacy outcomes. Pralsetinib (n=110) SOC(n=113) Stratified hazard ratio/odds ratio (95% CI) P Value Duration of follow-up, mo, median (range) 20.5(0, 49.8) 16.0(0, 42.3) - - PFS, mo, median (95% CI) 18.7(11.1, 25.2) 9.0(7.1, 11.5) 0.59(0.42, 0.84) 0.003 ORR, % (95% CI) 65.5(55.8, 74.3) 41.6(32.4, 51.2) 2.81(1.61, 4.93) &lt;0.001 OS, mo, median (95% CI) NR (29.6, NR) 39.8(39.8, NR) 1.09(0.65, 1.85) 0.742 DOR, mo, median (95% CI) 20.6(17.2, 31.8) 9.7(7.6, 15.9) 0.48(0.28, 0.80) 0.004

Outside Back Cover: Domino Polymerization for the Synthesis of Reductively Degradable Poly(disulfide)s With Arbitrary Side‐Chain Structures (Angew. Chem. Int. Ed. 23/2026)

Boosting Built‐in Electric Field via COF Molecular Quadrupole Gradients for Efficient H ₂ O ₂ Photosynthesis

ABSTRACT Covalent organic frameworks (COFs) are promising photocatalysts for hydrogen peroxide (H 2 O 2 ) generation using only water, air, and light. The intrinsic polarization, typically evaluated by the dipole moment of the photocatalyst, can induce a built‐in electric field to promote exciton dissociation and carrier migration. However, the dipole moment is negligible in a symmetric and periodic COF structure, which hinders the regulation of the built‐in electric field and efficient photocatalysis. In this work, we modulate the quadrupole moment by molecular engineering at specific COF sites to enhance the local electric field, achieving a remarkable H 2 O 2 photosynthesis rate of 8.32 mmol g −1 h −1 in pure water without any sacrificial agent. The local electric field and carrier dynamics studies unveil that the quadrupole moment gradient tunes the intrinsic carrier decay, fluorescence reabsorption, and exciton binding energy to optimize carrier utilization efficiency. Moreover, the stronger quadrupole moment can stabilize the adsorbed · OOH intermediate through polarization and electron redistribution. This work provides a molecular engineering strategy for local electric field manipulation and reveals fundamental relationships between the quadrupole moment and photocatalytic processes in non‐polar COF photocatalysts.

Eco-friendly synthesis of Ag/ZnO nanocomposite using Coleus amboinicus: Structural characterization and evaluation of antibacterial and anticancer activities

Optimization of gamma-ray irradiation for oxalic acid degradation through energy based cost analysis and hybrid strategy design

Iron-sulfur cofactors in nucleic acid metabolism and protein synthesis: Assembly, delivery, and putative roles in cellular and viral systems

Empegfilgrastim for primary febrile neutropenia prophylaxis during induction chemotherapy with docetaxel, cisplatin, and 5-fluorouracil in head and neck squamous cell carcinoma.

e18030 Background: Induction chemotherapy (CT) with docetaxel, cisplatin, and 5fluorouracil (DCF) before chemoradiotherapy can improve disease control in advanced head and neck squamous cell carcinoma (HNSCC) but is associated with a high risk of severe hematologic toxicity, including febrile neutropenia (FN). Empegfilgrastim is a long-acting granulocyte colony stimulating factor (GCSF) designed to reduce chemotherapy-induced neutropenia and FN. This single-center retrospective study evaluated the incidence of neutropenic complications in HNSCC patients (pts) receiving DCF induction CT with primary FN prophylaxis using empegfilgrastim. Methods: This was a retrospective, single-center cohort of pts with unresectable stage III/IVA hypopharyngeal, laryngeal, or oropharyngeal squamous cell carcinoma treated with 3 cycles of DCF induction CT (docetaxel 75 mg/m² day 1, cisplatin 75 mg/m² day 1, 5fluorouracil 1000 mg/m²/day as a continuous infusion on days 1–4, every 3 weeks), followed by empegfilgrastim 7.5 mg subcutaneously on days 4–8 of each cycle. The primary endpoint was the incidence of grade 3–4 neutropenia (CTCAE v5.0). Secondary endpoints included incidence of FN, nonhematologic adverse events (AEs) grade ≥3, and tumor response after induction CT. Results: A total of 55 pts with unresectable stage III/IVA HNSCC were included: hypopharynx (n=33), larynx (n=8), and oropharynx (n=14). The median age was 60 years (range 39–77); 83% had ECOG performance status 0–1 and 85% were male. Most pts (48/55, 89%) completed all 3 planned DCF cycles. Objective response was assessable in 32 pts, of whom 70% achieved an objective response, including 13 complete responses; the median change in target lesion size was −60% (range −84% to −28%). Grade 3–4 neutropenia occurred in 6 pts (11%), and FN in 4 pts (7.3%). The incidence of any nonhematologic AE grade ≥3 was 3/55 (5%). Conclusions: Primary prophylaxis with empegfilgrastim during DCF induction CT was associated with a relatively low incidence of grade 3–4 neutropenia and FN in pts with advanced HNSCC, while allowing the majority to complete planned treatment. Further analyses are planned to compare the efficacy and safety of empegfilgrastim administration on day 2 versus day 3 of the DCF regimen.

Real-world overall survival with mirvetuximab soravtansine compared with chemotherapy after multiple lines of platinum therapy in gynecologic cancers.

e17567 Background: Mirvetuximab soravtansine (MIRV) is FDA-approved for FRα-high, platinum-resistant ovarian cancer, with improved survival demonstrated in randomized trials. However, real-world comparative outcomes in heavily pretreated patients remain limited. We evaluated overall survival (OS) with MIRV versus standard chemotherapy following multiple platinum exposures in routine clinical practice. Methods: Using the TriNetX database (2020–2025), we identified adults with ovarian, fallopian tube, or primary peritoneal cancer who received at least three prior platinum therapies. To enrich for platinum-sensitive or partially sensitive disease, patients were required to receive a subsequent platinum agent within 7–180 days of initial platinum therapy before index treatment. Patients subsequently treated with MIRV or investigator’s choice chemotherapy (paclitaxel, pegylated liposomal doxorubicin, or topotecan) were included. FRα status was unknown. Cohorts were propensity score–matched (1:1) on demographics, comorbidities, disease characteristics, prior treatments, and laboratory values. OS was assessed from treatment initiation and capped at 4 years. Kaplan–Meier and Cox proportional hazards models were used. Results: Before matching, 559 MIRV and 11,508 chemotherapy patients met inclusion criteria; 515 patients per group were analyzed after matching. MIRV was associated with a modest but statistically significant OS advantage compared with chemotherapy (4-year survival 47% vs 46%; median OS 44.2 vs 39.9 months; HR 0.80, 95% CI 0.65–0.99; p = 0.0346). One-year survival was higher with MIRV (88% vs 82%; p = 0.0224). Among MIRV-treated patients, 185 subsequently received bevacizumab, with a median time to initiation of 6.9 months. Conclusions: In a heavily pretreated, platinum-exposed real-world population, MIRV demonstrated a small but significant survival advantage over standard chemotherapy. These findings support MIRV’s clinical benefit in later-line practice and highlight frequent post-MIRV bevacizumab use. Further studies are warranted to define optimal sequencing and combination strategies.

Deep learning–based classification of benign and malignant breast lesions on ultrasound using knowledge distillation with external validation and global deployment.

556 Background: Breast cancer is the most common malignancy in women worldwide. Although breast ultrasonography is widely accessible, diagnostic accuracy remains limited by operator dependence and interobserver variability (κ≈0.6–0.8), contributing to delayed diagnosis and unnecessary biopsies. While deep learning has shown promise in ultrasound-based lesion classification, many models are computationally intensive and lack external validation, limiting clinical scalability. We developed a deployment-ready deep learning framework that balances diagnostic performance with computational efficiency using structured knowledge distillation. Objectives: To develop and externally validate a computationally efficient deep learning model for binary breast ultrasound lesion classification; to evaluate whether a distilled student model preserves clinically meaningful performance from a high-capacity teacher network; and to assess global clinical feasibility through independent radiologist evaluation. Methods: We analyzed 8,116 breast ultrasound images (4,074 benign; 4,042 malignant) independently annotated by two board-certified radiologists with consensus adjudication. A ResNet34 teacher network (21.8M parameters) was trained using ImageNet-pretrained weights. A lightweight ResNet18 student network (11.7M parameters; 46% reduction) was trained using structured knowledge distillation with confidence-aligned soft targets and KL-divergence regularization. External validation was performed on three independent ultrasound datasets not used during training. Performance metrics included accuracy, sensitivity, specificity, precision, F1 score, and AUROC. The model was deployed in a HIPAA-compliant cross-platform application and independently evaluated by physicians across six continents. Results: The student model achieved 91.9% accuracy on held-out test data with balanced performance (sensitivity 90.8%, specificity 93.0%, F1 score 0.918). External validation demonstrated stable generalization (accuracy 89–92%). In global clinical deployment, 94.2% of participating physicians rated the system clinically useful and suitable for integration into routine breast ultrasound workflows. Conclusions: Knowledge distillation enables substantial model compression while preserving diagnostic accuracy for breast lesion classification on ultrasound. This scalable, deployment-ready approach supports standardized interpretation across diverse clinical environments and warrants prospective evaluation for reducing unnecessary biopsies and improving diagnostic efficiency.

Extracellular matrix-derived liquid biopsy for predicting response in patients with biliary tract cancer treated with nivolumab with or without ipilimumab combined with stereotactic body radiotherapy: Insights from the CheckPAC trial.

3043 Background: Biliary tract cancer (BTC) is a rare malignancy with limited treatment options and poor prognosis. Although combined chemotherapy and immune checkpoint inhibitors are first-line treatment for advanced BTC, durable response is uncommon. Current immunotherapy biomarkers, such as PD-L1 expression, have limited utility and treatment response biomarkers are urgently needed. BTC is characterized by a fibrotic extracellular matrix, where widespread tumor fibrosis has been linked to immunosuppression and treatment resistance. In this study, we used Nordic ProteinFingerPrint Technology to evaluate the pharmacodynamic and predictive value of the FDA supported fibrosis biomarker NordicPRO-C3 (type III collagen pro-peptide) and the T-cell infiltration biomarker NordicC4G (granzyme B degraded type IV collagen) in patients with metastatic BTC treated with nivolumab with or without ipilimumab plus stereotactic body radiotherapy (SBRT). Methods: PRO-C3 (NordicPRO-C3) and C4G (NordicC4G) were measured at baseline and 60 days after treatment initiation in serum from 61 patients with BTC from the CheckPAC trial (NCT02866383). Patients received SBRT combined with nivolumab (n = 19) or nivolumab/ipilimumab (n = 42). The primary endpoint was clinical benefit rate (CBR; CR+PR+SD vs. PD) assessed by RECIST 1.1. Biomarker levels at baseline and biomarker changes during therapy were evaluated relative to response using Fisher’s exact test; overall survival (OS) was assessed using uni- and multivariate Cox regression. Results: CBR was 0% in patients with high baseline PRO-C3 (243 ng/mL) versus 31% in patients with low PRO-C3 (p &lt; 0.05). High PRO-C3 was associated with poor OS after adjusting for CA19-9, performance status, and modified Glasgow Prognostic Score (HR = 3.1, 95% CI 1.5-6.6, p = 0.004). Longitudinally, C4G increased significantly at day 60 in patients with clinical benefit (p &lt; 0.001). CBR was 44% in patients with increased C4G versus 0% in those with decreased C4G (p = 0.007), and increased C4G was associated with improved OS (p = 0.01). All patients with clinical benefit had both increased C4G and low PRO-C3 at day 60. Among patients without clinical benefit, patients with increased C4G and low PRO-C3 and showed a trend towards improved OS (Median OS 8.3 months vs. 3.6 months, p = 0.08). Conclusions: High pre-treatment tumor fibrosis, quantified by elevated serum PRO-C3, is associated with poor response and OS in patients with BTC treated with SBRT plus immunotherapy. Changes in PRO-C3 and the T-cell infiltration biomarker C4G reflect pharmacodynamic changes, with increased C4G linked to improved outcome, particularly in patients with low PRO-C3. Together, these biomarkers may help to predict treatment response and guide clinical decision-making in BTC.

TAMS in appendiceal cancer: Association with metabolic remodeling, prognosis, and response to intra-tumoral therapy.

3597 Background: Appendiceal cancer (AC) is a rare malignancy with a distinct immunobiology and propensity for peritoneal metastasis. Tumor-associated macrophages (TAMs) are recognized as influential immune cells in various cancers. In this study, we sought to define the role of TAMs in AC, given its unique immune landscape and peritoneal microenvironment. Methods: Immunohistochemistry-quantified M1-like (CD68+CD86+) and M2-like (CD68+CD206+) TAM densities in 112 archival AC specimens were compared against clinicopathologic features and overall survival (OS). In parallel, a comprehensive tissue proteomic analysis (LC-MS/MS) was performed. Gene set enrichment analysis identified proteomic signatures associated with M1 and M2 density. Independently prognostic proteins were identified via Cox regression. External validation was performed by correlating these proteomic signatures in independent tumor samples from the RIOT-1 clinical trial (NCT05751837), in which AC patients received intra-tumoral lipopolysaccharide (LPS), a TLR4 agonist. Results: M2-like TAMs outnumbered M1-like TAMs in AC (p = 0.0002), particularly in peritoneal metastases (p = 0.002), and were not associated with tumor grade or histology. Low M1 density ( &lt; 18th percentile) correlated with worse OS (HR: 3.26, p = 0.03), while high M2 density ( &gt; 52nd percentile) was associated with improved OS (HR: 0.1, p = 0.03). A combined high-M1/M2 percentile metric was highly prognostic of favorable OS (p &lt; 0.001), independent of age, grade, and disease extent. On proteomic analysis, M1-rich tumors exhibited high bioenergetic demands, extensive metabolic reprogramming (isoprenoid/amino acid metabolism), retinol/xenobiotic metabolism, while M2-rich tumors emphasized ECM remodeling, profound amino acid metabolism (immunosuppressive), oxidoreductase activity, and complement activation, with suppressed cell motility. The combined high-M1/M2 phenotype correlated with intense amino acid/lipid metabolism and redox homeostasis. Five TAM-related, independently prognostic proteins were identified: GATD1 (favorable, HR 1.53x10-16), and AGR2, ENOPH1, RHOA, SERPINB6 (adverse, HRs 5.51-10.39). In RIOT-1, intra-tumoral LPS increased M1/M2 TAM infiltration and induced proteomic changes significantly correlated with M1-related (p = 0.0016), M2-related (p = 0.008), and combined TAM signatures (p = 0.047), supporting therapeutic tractability. Conclusions: AC harbors a TAM-rich immune microenvironment in which M2-like TAMs and a combined M1/M2 phenotype paradoxically associate with favorable prognosis. Distinct TAM-linked metabolic programs and validated prognostic proteins suggest clinically relevant biologic underpinnings of these findings, while modulation of the AC microenvironment via regional innate immune activation may represent a promising therapeutic strategy.