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Perioperative durvalumab plus neoadjuvant chemoradiotherapy (CROSS) with and without tremelimumab in esophageal adenocarcinoma: The prospective phase II RICE trial (NCT04159974).

4083 Background: Anti-PD-(L)1 is effective in esophageal adenocarcinoma (EGA). The phase II RICE trial (NCT04159974) evaluated the addition of neoadjuvant and adjuvant durvalumab, with or without tremelimumab, to neoadjuvant chemoradiotherapy (CROSS). Methods: Patients with locally advanced (≥uT3/Nx or uT2/N+) non-metastatic EGA received two doses of neoadjuvant durvalumab in addition to CROSS, followed by surgery. Adjuvant therapy was randomized 1:1 to durvalumab (12 doses) alone (arm A) or durvalumab plus one dose of tremelimumab (arm B). Translational analyses included HLA-I genotyping, immunohistochemistry, whole-exome sequencing and RNA-sequencing. Clinical outcomes were analyzed in patients who received at least one neoadjuvant dose (mITT) and in those who were randomized and received at least one adjuvant dose (R-mITT). Results: In the mITT set (n=56), 95% completed neoadjuvant therapy and 93% underwent resection. The rate of grade ≥3 non-hematologic adverse events during neoadjuvant treatment was 25% (13/56 G3, 1/56 G4). Surgery was feasible with a rate of anastomotic leakage of 6%. Major pathological response (MPR, <10% viable tumor cells) was achieved in 54% (30/56) including a 23% (13/56) pathological complete response rate (pCR, ypT0/ypN0). The rate of MPR was higher than in propensity-based comparisons with FLOT (25%) and CROSS (37%). Two-year overall (OS) and progression-free (PFS) survival of the mITT set were 72.7% and 53.1%, respectively. After completion of Stage I of the trial (safety run in), 38 patients were included in the R-mITT set. 80% in arm A (durvalumab monotherapy, n=20) and 44% in arm B (durvalumab plus tremelimumab, n=18) completed at least 80% of adjuvant immunotherapy. Combined immunotherapy in the R-mITT set was associated with higher grade ≥3 toxicity (22% G3/ 22% G4 in Arm B vs. 15% G3 / 0% G4 in arm A) and did not improve survival (2-year OS/PFS 95.0%/80.0% [arm A] vs. 82.4%/54.2% [arm B]). Tumor mutational burden, heterozygosity of HLA-I, expression of genes related to antigen presentation and T-cell abundance were associated with pathological response. However, discordant cases across all biomarkers underscore the complexity of tumor-immune interactions underlying response to immunotherapy. Conclusions: RICE demonstrates safety and feasibility of adding anti-PD-L1 to neoadjuvant CROSS in EGA and shows promising response rates. While CROSS is no longer considered standard of care, our results support efficacy of durvalumab, consistent with results for FLOT plus durvalumab in the MATTERHORN trial. Addition of tremelimumab to durvalumab is not supported by our study. Clinical trial information: NCT04159974 .

Short-course radiotherapy followed by ivonescimab and CAPOX as neoadjuvant therapy for locally advanced rectal cancer: A single-arm, phase II trial.

e15652 Background: Short-course radiotherapy (SCRT) combined with chemotherapy as neoadjuvant therapy has been proven to increase the pathological complete response (pCR) rate for locally advanced rectal cancer (LARC). Radiotherapy and immunotherapy exhibit a synergistic effect. Ivonescimab, a tetrameric bispecific antibody targeting PD-1 and VEGF, has the potential to produce synergistic anti-tumor effects. This study aimed to evaluate the efficacy and safety of SCRT followed by Ivonescimab and CAPOX as neoadjuvant therapy in LARC patients. Methods: In this single-arm, single-center, phase II trial, LARC patients who met at least one of the following high-risk criteria—cT4, cN2, EMVI (+), MRF (+) or lateral lymph node (+) —were enrolled. All patients should have a tumor inferior margin ≤10 cm above the anal verge, and received SCRT followed by 6 cycles of Ivonescimab (20mg/kg or 10mg/kg, Q3W) and CAPOX (capecitabine: 1000mg/m2, bid, po, d1-14; oxaliplatin: 130mg/m2, ivgtt, d1; Q3W). Surgery was performed 1 week after the completion of neoadjuvant therapy. The primary endpoint was the pCR rate, while the secondary endpoints include 3-years Event-Free Survival rate, R0 resection rate, quality of life, overall survival and safety. Results: As of December 25, 2025, a total of 49 patients were enrolled. Among these patients, 33(67.3%) were male, with a mean age of 59 years (range, 37-73). 25(51.0%) patients had cT4 disease, and 22(44.9%) had cN2. The rates of CRM (+), MRF (+) and EMVI (+) were 67.3%, 63.3% and 67.3%, respectively. Tumor response was evaluable in 42 patients, among whom 39 underwent surgical resection. The pCR rates were 48.7% (19/39), while the complete response rates (pCR + cCR) were 47.6% (20/42). All surgical procedures achieved R0 resection. During the neoadjuvant treatment period, treatment-related adverse events (TRAEs) of any grade occurred in all patients (100%). The most common TRAEs were lymphocyte count decreased (100%), anemia (93.9%), weight loss (73.5%), and anorexia (73.5%). Grade ≥3 TRAEs were observed in 67.3% of patients, with the most common being lymphocyte count decreased (46.9%), anemia (22.4%), and weight loss (16.3%). Conclusions: SCRT followed by Ivonescimab and CAPOX as neoadjuvant therapy in LARC patients seems to demonstrate safety and promising efficacy. Clinical trial information: NCT06802666 . Surgical and post-operative pathological outcomes. Surgical population N=39 Pathological complete response (ypT0N0), n(%) 19(48.7) Tumor regression grading, n (%) 0 19(48.7) 1 12(30.8) 2 7(17.9) 3 1(2.6) Pathological tumor stage, n (%) ypT0 19(48.7) ypTis 1(2.6) ypT1 3(7.7) ypT2 5(12.8) ypT3 10(25.6) ypT4 1(2.6) Pathological node stage, n (%) ypN0 35(89.7) ypN1 3(7.7) ypN2 1(2.6) Surgical resection status, n (%) R0 39(100)

Oral darolutamide therapy in patients with metastatic hormone-sensitive prostate cancer (mHSPC): A systematic review and meta-analysis of phase III randomized controlled trials.

e17095 Background: Prostate cancer (PCa) is one of the most common malignancies among men globally and remains a leading cause of cancer mortality. It is the second most prevalent solid tumor in men and the fifth most common cause of cancer-related deaths. Darolutamide is a next-generation nonsteroidal androgen receptor antagonist designed to have potent AR blockade with minimal CNS penetration. The study aims to assess the efficacy and safety of oral darolutamide therapy in men with hormone-sensitive prostate cancer. Methods: A comprehensive literature search was conducted across PubMed, Cochrane, Scopus, Embase, and ClinicalTrials.gov from inception to November 2025, selecting studies based on predefined eligibility criteria, following PRISMA guidelines. Time-to-event outcomes were pooled as Hazard Ratios (HR) with 95% confidence intervals (CI) using fixed-effect models for outcomes with low heterogeneity, and random-effects models to account for potential heterogeneity. Sensitivity analyses were also performed for outcomes with moderate to high heterogeneity. Heterogeneity was assessed using I² and X² statistics, with a p-value of < 0.05 considered statistically significant. All calculations were performed using RevMan 5.4. Results: A total of 13 Randomized Controlled trials were included in the study. Analysis demonstrated that darolutamide was associated with a statistically significant improvement in overall survival compared with control therapy (HR = 0.62, 95% CI 0.55–0.70; p < 0.00001). Funnel plot inspection did not reveal any marked asymmetry. It significantly prolonged the time to castration-resistant prostate cancer compared with control treatment (HR = 0.38, 95% CI 0.35–0.42; p < 0.00001; I² = 0%). Various other outcomes with statistically significant results are as follows: time to PSA progression (HR = 0.29, 95% CI 0.24–0.35; p < 0.00001, I² = 26%), time to pain progression compared with control therapy (HR = 0.55, 95% CI 0.34–0.89; p = 0.02), and delay in time to subsequent systemic therapy compared with control treatment (HR = 0.39, 95% CI 0.34–0.45; p < 0.00001, I² = 0%). No heterogeneity was observed among included studies (I² = 0%), and there was a prolongation in time to first symptomatic skeletal event (HR = 0.74, 95% CI 0.63–0.87; p = 0.0003, I² = 0%). Funnel plot inspection did not demonstrate asymmetry. The incidence of adverse events and serious adverse events was comparable between the darolutamide therapy and control groups across the included studies. Conclusions: Thus, oral darolutamide therapy was associated with statistically significant improvements in overall survival and multiple disease progression-related outcomes in men with hormone-sensitive prostate cancer. Limited sample sizes and short follow-up necessitate larger studies to confirm its efficacy and safety.

Cohort expansion of a phase I study of PLN-101095, a first-in-class dual α _v β ₈ /α _v β ₁ integrin inhibitor, in combination with pembrolizumab in patients with advanced solid tumors refractory to immune checkpoint inhibitors (ICI).

TPS2690 Background: Transforming growth factor-β (TGF-β) drives immunosuppression and T-cell exclusion in solid tumors and contributes to immune checkpoint inhibitor (ICI)-acquired resistance. The integrins α v β 8 and α v β 1 activate latent TGF-β in the tumor microenvironment, promoting immune escape. PLN-101095 is a first-in-class, oral dual α v β 8 /α v β 1 inhibitor designed to block TGF-β activation and restore antitumor immunity in patients with advanced solid tumors refractory to prior ICI. Part 1 of our study (NCT06270706) employed a Bayesian optimal interval design for dose escalation. The Part 2 expansion cohorts were driven by Part 1 efficacy signals, including 4 responders with secondary resistance to ICI, most of whom had high tumor mutational burden (TMB-H) prior to baseline. Methods: This is an ongoing Phase 1 open-label multicenter study conducted in the United States. Part 1 (dose escalation) enrolled patients with advanced or metastatic solid tumors who had either primary or secondary resistance to prior ICI. Part 2 (dose expansion) will enroll only patients meeting Society for Immunotherapy of Cancer (SITC) criteria for secondary resistance to prior ICI therapy based on a Simon 2-stage design. The Part 2 expansion cohorts will be as follows: 1) non-small cell lung cancer; 2) head and neck squamous cell carcinoma; 3) clear cell renal cancer; and 4) TMB-H tumors (historical ≥10 mutations/megabase, as determined by local testing with a Clinical Laboratory Improvement Amendments–certified next-generation sequencing [NGS] assay). The target sample size for cohorts 1-3 is 19 patients each, and the target for cohort 4 is 36 patients. The primary endpoints are objective response rate (ORR) and disease control rate (DCR) per immune RECIST. The secondary endpoints are pharmacokinetics (PK), safety and tolerability, and duration of response (DOR). Planned exploratory biomarkers analyses include characterization of integrin expression, TGF-β and immune-related gene expression, and tumor microenvironment (TME) in tumor biopsies. Plasma cytokine profiling and circulating tumor DNA (ctDNA) will also be examined. Clinical trial information: NCT06270706 .

Epidemiological trends in colorectal cancer mortality in South Asia, 1990–2023: A retrospective analysis and advanced machine learning forecasting to 2050.

e15591 Background: Colorectal cancer (CRC) is an emerging cause of cancer mortality in South Asia, yet comprehensive long-term trend analyses incorporating sex-specific patterns and future projections are limited. We evaluated historical CRC mortality trends and forecasted future burden across South Asia from 1990 to 2050. Methods: We conducted a retrospective population-based analysis of age-standardized mortality rates (ASMRs) for CRC across South Asia between 1990 and 2023, from the Global Burden of Disease 2023 database, stratified by country and sex. Temporal trends were quantified using estimated annual percentage change (EAPC) with 95% confidence intervals (CIs). Machine learning–based ARIMA time-series models were applied to project ASMRs through 2050 with uncertainty intervals. Results: From 1990–2023, CRC mortality increased significantly across South Asia (both sexes EAPC 0.60; 95% CI 0.47–0.73), with higher growth among males (EAPC 0.78; 95% CI 0.65–0.91) than females (0.43; 95% CI 0.27–0.58). Pakistan showed the steepest increase (both sexes EAPC 1.12; 95% CI 1.01–1.23), followed by Bangladesh (1.00; 0.80–1.21), India (0.49; 0.36–0.63), and Bhutan (0.44; 0.35–0.53). Nepal demonstrated near-stable trends (both sexes EAPC 0.06; −0.16 to 0.29), with declining female mortality (−0.20; −0.45 to 0.05). In Pakistan, male ASMRs rose from 3.79 (1990) to 5.37 per 100,000 (2023) and are projected to reach 6.64 (95% UI 5.21–8.07) by 2050; female ASMRs increased from 6.61 to 8.76 and are forecast to reach 10.51 (8.65–12.37). In Bangladesh, both-sex ASMRs increased from 4.61 (1990) to 7.59 (2023) and are projected to nearly double by 2050 (14.92; 6.14–23.70), driven by rapid rises among females. India showed moderate increases, with male ASMRs stabilizing after 2023 (~5.55), while female ASMRs rose from 4.12 to 4.88 and are projected to plateau near 4.9–5.0 after 2030. Conclusions: CRC mortality has risen steadily across South Asia over the past three decades, with marked male predominance and substantial inter-country heterogeneity. Forecasts indicate a sustained and disproportionate future burden in Pakistan and Bangladesh, underscoring the urgent need for population-level screening, early detection strategies, and equitable access to oncologic care. Location Sex EAPC Lower 95%CI Upper 95%CI Bangladesh Both 1.00 0.80 1.21 Bangladesh Female 0.56 0.27 0.86 Bangladesh Male 1.36 1.22 1.51 Bhutan Both 0.44 0.35 0.53 Bhutan Female 0.26 0.14 0.39 Bhutan Male 0.64 0.58 0.70 India Both 0.49 0.36 0.63 India Female 0.34 0.18 0.50 India Male 0.67 0.52 0.82 Nepal Both 0.06 -0.16 0.29 Nepal Female -0.20 -0.45 0.05 Nepal Male 0.33 0.12 0.53 Pakistan Both 1.12 1.01 1.23 Pakistan Female 1.02 0.90 1.15 Pakistan Male 1.12 1.00 1.25 South Asia Both 0.60 0.47 0.73 South Asia Female 0.43 0.27 0.58 South Asia Male 0.78 0.65 0.91

Treatment patterns and oncologic outcomes in patients with triple-negative (TN) lobular breast cancer.

605 Background: Triple-negative breast cancer (TNBC) with invasive lobular carcinoma (ILC) histology represents an exceedingly rare (<1% of breast cancers) and aggressive disease subtype with poorly described outcomes. In an effort to better understand treatment patterns and prognosis for these patients, we conducted an analysis using the National Cancer Database to assess treatments and outcomes in this high-risk, understudied population. Methods: We identified patients ≥18 years with stage I-III TNBC diagnosed between 2017-2022 who underwent mastectomy or lumpectomy with ILC or invasive ductal histology (IDC) (n=80,589). Of these patients, 69,940 were treated with chemo- or immunotherapy (CTx/IO). Subgroup analysis included patients treated with neoadjuvant chemotherapy (NACT) ± IO (n=47,822). Among this subgroup, trends in NACT±IO and pathologic complete response (pCR) rates by histology were assessed using the Cochran-Armitage test. Associations between histology and NACT use or pCR were evaluated with multivariable logistic regression. Impact of pCR on overall survival (OS) was examined via Kaplan-Meier estimates and multivariable Cox models with propensity score weighting and matching (1:1 by stage and NACT type). Results: Among 80,589 patients with TNBC (median age 58 years), 79,645 (98.8%) had IDC and 944 (1.2%) had ILC. Patients with ILC were older (66 vs 58 years) and less likely to receive CTx/IO compared to those with IDC (75.5% vs 86.9%). Among 69,940 patients treated with CTx/IO, those with ILC were older (median age 65 vs 56 years), had higher clinical tumor stage, and were less likely to receive NACT compared to those with IDC (61.9% vs 68.4%; p<0.001). Among 47,822 patients who received NACT ± IO, patients with ILC had significantly lower pCR rates (16.1% vs 40.2%; aOR=0.44, 95% CI 0.34-0.57). The addition of IO showed a trend toward improved pCR rates in ILC (aOR=1.69, 95%CI 0.95-3.01, p=0.07). In 29,330 matched patients, pCR was associated with improved 5-year OS (94% vs 78%, p<0.001). However, in 108 matched ILC patients, no survival difference was observed by pCR status (5-year OS: 66% with pCR vs 69% without pCR, p=0.54). In a multivariable Cox model with inverse probability weighting among patients who received NACT±IO, ILC was associated with increased mortality risk (aHR=1.34, 95%CI 1.05-1.70, p=0.02), after adjustment for pCR, IO, age, race, tumor size, and insurance status, among other factors. Conclusions: Patients with TN-ILC who received NACT had lower pCR rates and worse OS compared to those with TN-IDC. Although limited by small sample size, this is the largest analysis of its type in the current NACT and IO era. These data suggest that pCR in TN-ILC may lack the prognostic significance it has in TN-IDC. These findings highlight the need for larger studies and novel therapeutic approaches tailored to the distinct biology of this rare subtype.

Malnutrition and cachexia as drivers of failure-to-rescue in gynecologic cancer hospitalizations, 2016–2023.

11053 Background: Malnutrition and cancer cachexia are underrecognized in administrative data yet may identify hospitalized oncology patients with limited physiologic reserve. Rather than acting solely as baseline comorbidities, these conditions may amplify the lethality of inpatient complications. The prevalence, temporal trends, and outcome-modifying role of malnutrition were evaluated among U.S. gynecologic oncology hospitalizations using a failure-to-rescue framework. Methods: A retrospective, survey-weighted analysis of the National Inpatient Sample (NIS), 2016–2023, was conducted. Adult hospitalizations with gynecologic malignancies (ICD-10-CM C51–C58) were included; palliative encounters (Z51.5) were excluded. Malnutrition was defined using a narrow phenotype (E43, E44.*, E46) and a broader definition including cachexia (R64). Outcomes included in-hospital mortality, ICU escalation (mechanical ventilation and/or shock), major complications (sepsis, bleeding/transfusion, venous thromboembolism, acute kidney injury, bowel injury/peritonitis, respiratory failure), length of stay (LOS), hospitalization cost, and failure-to-rescue (death following ≥1 complication among surgical admissions). Survey-weighted estimates with 95% confidence intervals (CI) were reported. Results: The cohort included 1,019,030 weighted hospitalizations. Malnutrition prevalence was 12.75% (95% CI, 12.53–12.98) using the narrow definition and increased from 9.61% in 2016 to 15.32% in 2023. In-hospital mortality was higher among malnourished admissions (4.36% [95% CI, 4.11–4.63] vs 1.55% [95% CI, 1.48–1.61]). Malnutrition was associated with greater ICU escalation (5.63% [95% CI, 5.35–5.92] vs 2.48% [95% CI, 2.41–2.56]), AKI (31.53% [95% CI, 30.93–32.13] vs 17.54% [95% CI, 17.33–17.76]), and any major complication (64.97% [95% CI, 64.35–65.60] vs 44.07% [95% CI, 43.74–44.40]). Resource utilization was higher with malnutrition (LOS 8.98 vs 4.71 days; cost $28,155 vs $18,740). Among admissions with complications, mortality was higher with malnutrition (6.27% [95% CI, 5.90–6.65] vs 3.16% [95% CI, 3.03–3.29]). In the surgical subcohort, failure-to-rescue mortality was 2.55% (95% CI, 1.98–3.28) with malnutrition versus 0.82% (95% CI, 0.70–0.95). Conclusions: In U.S. gynecologic oncology hospitalizations, malnutrition and cachexia identify a high-risk inpatient phenotype with disproportionate complication burden and post-complication mortality. These findings support malnutrition as a modifier of failure-to-rescue rather than an isolated baseline risk factor and highlight inpatient nutritional vulnerability as a target for early risk stratification and supportive intervention.

Association of sociodemographic, environmental, and health factors with early-onset cancer in a diverse urban cohort.

10592 Background: Early onset cancer (EOC; diagnosed before age 50) is rising globally, yet its drivers are incompletely understood, especially in diverse community-based populations. We examined sociodemographic, environmental, and health factors associated with EOC in the community-based Chicago Multiethnic Prevention And Surveillance Study (COMPASS) cohort spanning 72 Chicago neighborhoods. Methods: This nested case-control study within COMPASS matched EOC cases to controls without cancer 1:2 by age and sex. Standardized mean differences (SMD) compared sample characteristics. Conditional logistic regressions evaluated EOC associations with odds ratios (OR) and 95% confidence intervals (CI), adjusted for race/ethnicity. Meaningful imbalance was defined as SMD>0.2 and statistical significance as p<0.05. Results: Among 13,309 COMPASS participants, 265 EOC cases were matched to 530 controls. While the full sample was well balanced by sex (51.4% male), cases were predominantly female (72.8%) and non-Hispanic Black (72.3%). Breast (28.3%) and cervical (16.2%) cancers were most reported. A greater proportion of cases identified as unemployed/disabled but were also college educated and with incomes ≥$35,000 (SMD=0.382, 0.326, 0.267). Parental cancer history was more common in cases (SMD=0.504). No imbalances were observed in neighborhood-level characteristics, including area deprivation index, particulate matter concentration, and healthcare access strain. Cases reported more recent mammography and prostate-specific antigen screening (SMD 0.385, 0.407) but not pap smears (SMD=0.195). Cigarette use did not differ (SMD=0.141). Cases had higher prevalence of type 2 diabetes (T2D), anxiety, and depression (SMD=0.216, 0.302, 0.242), and lower prevalence of allergies (SMD=0.229). EOC was associated with parental cancer history (OR=3.62, CI 2.31-5.67, p<0.001), T2D (OR=1.65, CI 1.02-2.69, p=0.043), and anxiety (OR=2, CI 1.24-3.23, p=0.005), but not sociodemographic or neighborhood factors. Conclusions: In this diverse cohort, EOC was associated with multiple factors, including family cancer history, breast/prostate screening, and select health comorbidities. No associations were observed with reported neighborhood-level environmental metrics, current tobacco use, or cervical cancer screening. Our results highlight challenges in measuring sociodemographic and environmental contributors to EOC. Our results align with existing hypotheses on cancer development: familial risk, the potentially protective role of allergies, and T2D-related cancer risk. While causality cannot be inferred, the observed EOC-screening and EOC-anxiety associations warrant further investigation with longitudinal, multilevel research to better define EOC drivers and inform EOC prevention and detection strategies.

Prospective-retrospective HeCOG phase III trial validation of Polaris TME for the prediction of TILs from whole-slide images in high-risk early breast cancer.

557 Background: Tumor-infiltrating lymphocytes (TILs) are an established prognostic and predictive biomarker in early breast cancer. However, manual histopathologic scoring can introduce interobserver variability and limit throughput in analyzing at scale in routine practice. Recent advances in artificial intelligence (AI) offer the potential to standardize TILs quantification and enhance reproducibility. Our aim is to evaluate whether deep learning-based tumor microenvironment (TME) quantification from digitized hematoxylin- and eosin (H&E)-stained slides can accurately classify TILs and assess their prognostic role in patients with early breast cancer. Methods: We conducted a prospective-retrospective external validation of Polaris TME, a deep learning model for TME quantification. The analysis included patients with high-risk early breast cancer treated with adjuvant contemporary dose-dense chemotherapy, spanning all histological subtypes, enrolled in four HeCOG trials conducted between 1997 and 2008 (3 randomized and 1 observational). Manual TILs scoring had been centrally performed by pathologists according to International TILs Working Group guidelines, enabling direct comparison between manual and AI-derived scoring. The Polaris foundation model was used for feature extraction, while model performance was assessed using correlation for continuous TILs scores using the Spearman ρ and discrimination for clinically defined TILs categories (thresholds: 5% and 50% using the Area Under the Curve (AUC) with 95% CI. The prognostic value of the model was assessed using the log-rank test for invasive disease-free survival (iDFS). Results: Overall, 1,214 patients with whole slide images, TILs quantification and follow-up data were included; median age 53 [22-79]; 638 (63%) were hormone receptor-positive/HER2-negative, 394 (32%) HER2-positive, 176 (14%) triple-negative breast cancer (TNBC), and 6 patients of unknown subtype. Median follow-up was 116.59 (53.45 –157.06) months. When blindly deployed on the external cohorts, the model showed a significant correlation with the manual TILs scoring (ρ=0.60, p<0.001). The model yielded an AUC of 0.78 (0.75–0.81) for >5% TILs and AUC of 0.92 (0.88–0.95) for the >50% TILs. Predicted low-TILs tumors were associated with significantly lower 10-year iDFS in TNBC (55.1% versus 70.9%, p=0.034), with a similar pattern observed in HER2-positive (55.3% versus 64.8%, p=0.096), whereas there was no difference in 10-year iDFS between the predicted TILs groups for luminal cancers. Conclusions: These results indicate that Polaris TME accurately quantifies TILs derived from digitized H&E slides and provides prognostic measure for long-term iDFS in high-risk early breast cancer. Prospective validation and harmonization efforts to facilitate clinical implementation are warranted.

Engineering and preclinical evaluation of CXCR3-expressing, EGFR-targeted CAR-NK cells for tumor homing in non–small cell lung cancer and esophageal squamous cell carcinoma models.

e14515 Background: CAR-NK cell therapy for solid tumors is hindered by insufficient tumor infiltration. To address this limitation, we engineered anti-EGFR CAR-NK cells, which is overexpressed in non-small cell lung cancer and esophageal squamous cell carcinoma (ESCC)—to co-express the chemokine receptor CXCR3. This strategy aims to enhance homing to tumor microenvironments enriched with CXCR3 ligands CXCL9 and CXCL10. Methods: Third-generation anti-EGFR CAR constructs—either fused with CXCR3 via a P2A self-cleaving peptide (CAR-CXCR3) or co-expressed with IL-15 as a control (CAR-IL-15)—were generated. Primary human NK cells were lentivirally transduced and comprehensively characterized using: flow cytometry to assess CAR and CXCR3 expression and cellular purity; Annexin V/propidium iodide (PI)–based cytotoxicity assays against EGFR-positive A549 (NSCLC) and KYSE150 (ESCC) target cells; Transwell migration assays toward CXCL9 and CXCL10, followed by functional assessment of post-migration cytotoxicity; quantification of cytokine secretion (IFN-γ, granzyme B) and CD107a surface exposure (a marker of degranulation) upon co-culture with tumor cells; and in vivo evaluation of antitumor efficacy in NSG mice bearing subcutaneous KYSE150 tumors engineered to overexpress CXCL9/10. Mice received three intravenous doses (1 × 10⁷ cells per dose) of CAR-CXCR3-NK cells or phosphate-buffered saline (PBS) as control. Results: CAR-NK cells achieved ~50% transduction efficiency and > 93% purity. CXCR3 expression was robustly and selectively upregulated only in CAR-CXCR3-NK cells. Both CAR-NK variants exhibited potent, EGFR-dependent cytotoxicity significantly exceeding that of unmodified NK cells. CAR-CXCR3-NK cells demonstrated markedly enhanced migration toward CXCL9 and CXCL10 (68.2% vs. 32.5% migrated cells; p < 0.01), an effect fully abrogated by CXCR3 blockade, and retained strong cytolytic activity following migration. Upon engagement with tumor cells, CAR-CXCR3-NK cells secreted significantly higher levels of IFN-γ and granzyme B (p < 0.05) and displayed increased CD107a degranulation (p < 0.01). In vivo, CAR-CXCR3-NK treatment led to significant suppression of tumor growth (p < 0.001); CAR-NK cells were readily detectable in peripheral blood, and a trend toward prolonged survival was observed (median survival: 18.2 vs. 9.5 weeks; p = 0.06). No unexpected or off-target toxicities were noted. Conclusions: EGFR-directed CAR-NK cells co-expressing CXCR3 demonstrate enhanced chemotaxis toward CXCL9/10, superior in vitro cytotoxic function, and robust in vivo antitumor efficacy. Incorporating CXCR3 represents a promising and rationally designed strategy to overcome the critical barrier of poor tumor infiltration in CAR-NK therapy for EGFR-overexpressing solid malignancies.

Older age as a predictor of post-transplant survival in newly diagnosed acute myeloid leukemia treated with HMA-venetoclax.

6530 Background: Venetoclax (Ven) plus hypomethylating agents (HMA) is standard frontline therapy for newly diagnosed AML (ND-AML) patients unfit for intensive chemotherapy and is also being considered in younger and fit patients (Fathi, Blood 2025). However, consolidation with allogeneic stem cell transplant (ASCT) is often required to secure durable remission. The current study examines predictors of post-transplant survival (PTS) in the particular scenario. Methods: ND-AML patients who received upfront Ven+HMA and underwent ASCT were retrospectively studied. PTS, relapse rate, and non-relapse mortality (NRM) were evaluated. Results: 111 ND-AML patients (58% male, 60% secondary/therapy-related, median age 70 [37-80 years]) received median 3 cycles of Ven-HMA. 22% had complex karyotype. Mutations at diagnosis included RUNX1 (18%), SRSF2 (17%), TP53 (16%), ASXL1 , IDH2 , K/NRAS and TET2 (14% each), STAG2 (11%), DNMT3A (8%) and at time of ASCT (N=78 evaluable); RUNX1 (8%), NPM1 (6%), TP53 and ASXL1 (5% each), and SRSF2 and TET2 (4% each). At ASCT, all patients were in CR/CRi; 88% after Ven-HMA and 12% after additional bridging therapy. MRD by flow cytometry was detected in 18 (24%) of 76 evaluable patients and complex karyotype in 8 (9%) of 94. Donors were mostly HLA-matched unrelated (75%), with 51% receiving fludarabine/melphalan conditioning and 67% post-transplant cyclophosphamide (PTCy). At a median follow-up of 30 months, 42 patients (38%) have died including 18 (40%) from relapse. Median PTS was not reached (NR) with 1-2-3-year survival of 69%/60%57%. On multivariate analysis, age ≥65 years (median NR vs 10 months p<0.01), STAG2 (NR vs 44 months; p=0.04), and DNMT3A mutations (NR vs.NR p=0.05) were associated with superior PTS. In analysis limited to variables at time of ASCT, age ≥65 years remained significant (p<0.01) while TP53 mutations, donor type, and MRD status were not (p>0.1). Patients <65 years more often received bridging therapy compared to ≥65 years (23% vs 7%; p<0.05); excluding salvage-treated patients did not change survival results. 18 patients (16%) experienced post-ASCT relapse with median RFS of 7 months. Relapse rates at 1/2/3 years were 22%, 30% and 31% and NRM 13%, 24%, 46%, respectively. Patients <65 years had a higher 1 yr relapse incidence than those ≥65 years (36% vs 18%; p=0.01), with similar NRM (p=0.58). PTCy was not associated with relapse (p=0.66) but showed a borderline association with higher NRM (1-/2-/3-year 17%/31%/58% vs 4%/7%/16% in non-PTCy recipients; p=0.06). GVHD rate was 44% (50% ≥grade 2) with no association with relapse (p=0.43) or NRM (p=0.99). Conclusions: In the current study, older age (>65 years), including >75 years, was independently associated with superior PTS in ND-AML patients receiving Ven-HMA. By contrast, PTS was not affected by genetic profile at the time of ASCT, donor type, conditioning regimen, or GVHD prophylaxis.

RP2R dose selection of Tal + Tec for the treatment of EMD patients in the RedirecTT-1 study.

7524 Background: Talquetamab (Tal, anti-GPRC5D) and Teclistamab (Tec, anti-BCMA) are first-in-class bispecific antibodies approved as monotherapies for triple-class exposed relapsed/refractory multiple myeloma (RRMM). Extramedullary disease (EMD) is an aggressive MM subtype with poor outcomes and high unmet need. RedirecTT-1 (NCT04586426) is a Phase 1b/2 dose escalation/expansion study evaluating Tal + Tec in RRMM patients (pts) including EMD. We present data supporting selection of the recommended Phase 2 regimen (RP2R) for treatment of EMD pts, based on efficacy, safety, and exposure-response (E-R) analyses from Phase 1. Phase 2 allowed switching to a Q4W regimen after cycle 6 or cycle 4 if the response was ≥VGPR. Methods: Phase 1 evaluated 6 dose regimens of Tal (0.2–0.4 mg/kg QW, 0.8 mg/kg Q2W, 0.8 mg/kg Q4W) + Tec (0.75-1.5 mg/kg QW, 1.5-3 mg/kg Q2W, 3 mg/kg Q4W). Responses were investigator-assessed per IMWG criteria. CRS and ICANS were graded by ASTCT criteria; all other adverse events were graded by CTCAE v5.0. Model-based E-R analyses for efficacy were conducted with reported efficacy endpoints (ORR, ≥VGPR, ≥CR). First cycle PK metrics (C avgC1 , C troughC1 ) were used due to time-varying clearance of Tal and Tec. Results: At the clinical cutoff for this analysis (18 March 2025), Phase 1 enrolled 114 pts (38 EMD) with a median follow-up of 31.6 months. EMD pts treated with QW regimens of Tal 0.2-0.4 mg/kg + Tec 0.75-1.5 mg/kg (n=13), which comprised of multiple dose levels (1-9 pts per cohort), achieved an ORR of 33-100% (≥CR, 0-22.2%). EMD pts treated with the Q2W regimen using Tal 0.8 mg/kg and Tec 1.5 mg/kg (n=4) achieved an ORR of 50% (≥CR, 25%), while EMD pts treated with the Q2W regimen including Tal 0.8 mg/kg + Tec 3.0 mg/kg (RP2R, n=18) demonstrated high and deep response rates (ORR, 61.1%, ≥CR, 44.4%) with a manageable safety profile. EMD pts treated with the Q4W regimen of Tal 0.8 mg/kg + Tec 3.0 mg/kg (n=3) achieved an ORR of 100%, where 2 achieved ≥VGPR, but none achieved ≥CR. The RP2R generally provided higher and deeper responses in EMD pts compared to non-RP2R regimens. The efficacy E-R analysis for EMD pts showed a positive E-R relationship between exposure (C avgC1 and C troughC1 ) and ≥CR. Pts with exposures above the median for both Tal and Tec showed higher CR rates. At RP2R, C avgC1 and C trC1 exceeded median exposures across all Phase 1 dose regimens for both antibodies. The overall safety profile of Tal + Tec at the RP2R was manageable and consistent with each agent as monotherapy, while enabling deeper and more durable responses than observed across non-RP2R regimens. Conclusions: The totality of efficacy, safety and E-R analyses support advancement of a Tal + Tec regimen for further clinical development in RRMM pts with EMD who have received a PI, an IMiD, and an anti-CD38 mAb, and offers flexibility of switching to Q4W for responders. Clinical trial information: NCT04586426 .

Petosemtamab plus pembrolizumab as first-line (1L) treatment of PD-L1 high metastatic non-small cell lung cancer (NSCLC): Global phase 2 trial.

TPS8662 Background: NSCLC has a heterogeneous biology frequently including high mutational burden, high EGFR expression and upregulated EGFR signaling that is associated with poor prognosis. In the first-line metastatic setting, combination regimens pairing platinum-based chemotherapy with immune checkpoint blockade are standard of care; however, most patients experience disease progression within the first year. Petosemtamab is a low-fucose human common light chain, IgG1 bispecific antibody targeting EGFR and leucine-rich repeat-containing G-protein coupled receptor 5 (LGR5). Petosemtamab mechanism of action includes inhibition of EGFR ligand binding and downstream signaling, degradation of EGFR via LGR5 internalization in EGFR/LGR5-expressing cells, and immune system activation via enhanced ADCC (Herpers et al. Nat Cancer 2022; Lundberg et al. Cancers 2025). Petosemtamab plus pembrolizumab has previously demonstrated clinically meaningful efficacy and a manageable safety profile in 1L PD-L1-positive recurrent/metastatic head and neck squamous cell carcinoma (van Herpen et al. ASCO 2025). Methods: MCLA-158-CL04 (NCT07353957) is an open-label, multicenter, phase 2 trial to investigate petosemtamab in combination with pembrolizumab in squamous (Sq) and non-SqNSCLC. Two cohorts will be evaluated in patients with PD-L1 high (TPS ≥50%) metastatic sqNSCLC and non-sqNSCLC, respectively, with no prior systemic treatment for metastatic disease. Patients will be treated with petosemtamab 1500 mg IV Q2W in combination with pembrolizumab 400 mg IV Q6W. The primary objective is investigator-assessed objective response rate. Enrollment of approximately 80 patients in North America, EU, and Asia-Pacific is planned. Clinical trial information: NCT07353957 .

Objective responses and survival outcomes by grade 3-4 neutropenia in refractory metastatic colorectal cancer treated with trifluridine/tipiracil: Real-world evidence from the ReTrITA study.

e15611 Background: In refractory metastatic colorectal cancer (mCRC) treated with trifluridine/tipiracil (T), treatment-related neutropenia has been associated with improved survival. Whether this benefit is linked to objective response patterns in real-world practice remains unclear. This sub-analysis of the ReTrITA study evaluated survival outcomes according to objective response categories in patients stratified by grade 3-4 neutropenia. Methods: ReTrITA is a multicenter Italian real-world observational study including patients with refractory mCRC treated with T. Patients were stratified by the occurrence of grade 3/4 neutropenia (T neut vs T no-neut). Objective response was classified as partial response (PR), stable disease (SD), or progressive disease (PD). Overall survival (OS) and progression-free survival (PFS) were estimated using the Kaplan–Meier method and compared across response categories using log-rank tests (χ²). Results: Overall, 843 patients were included in this substudy, of whom 807 (95.7%) were evaluable for objective response, including 265 in the T neut group and 542 in the T no-neut group. In the T neut group, PR, SD, and PD were observed in 5.9% (n = 16), 28.8% (n = 76), and 63.1% (n = 167) of patients, respectively. Overall survival differed significantly across response categories (log-rank χ² = 57.08, df = 2; p < 0.0001), with median OS of 21.7 months for PR, 20.9 months for SD, and 8.5 months for PD. Progression-free survival showed a similar gradient (log-rank χ² = 82.83, df = 2; p < 0.0001), with median PFS of 10.5, 8.5, and 3.7 months, respectively. In the T no-neut group, PR, SD, and PD were documented in 1.0% (n = 5), 20.3% (n = 110), and 73.4% (n = 398) of patients, respectively. Median OS was 13.0 months for PR, 15.5 months for SD, and 6.5 months for PD, with significant separation of survival curves (log-rank χ² = 75.66, df = 2; p < 0.0001). Median PFS was 7.2, 7.1, and 3.0 months, respectively (log-rank χ² = 119.74, df = 2; p < 0.0001). Across corresponding response categories, patients who developed grade 3–4 neutropenia consistently experienced longer OS and PFS compared with those without neutropenia. Conclusions: In this large real-world cohort of patients with refractory mCRC treated with T, objective response categories were strongly associated with OS and PFS. The occurrence of grade 3–4 neutropenia identified patients with consistently improved survival across response strata, supporting its role as a prognostic and pharmacodynamic marker of treatment benefit beyond radiological response.

Beyond convolution: Vision transformer–based modeling for histopathological classification of colorectal carcinoma.

e15671 Background: Colorectal carcinoma (CRC) is a major contributor to global cancer morbidity and mortality, with histopathological evaluation remaining the diagnostic gold standard. However, CRC tissue exhibits marked architectural heterogeneity, multi-scale glandular patterns, and variable stromal composition, contributing to diagnostic variability and increased pathologist workload. Convolutional neural networks (CNNs) have demonstrated strong performance in CRC histology classification but are inherently limited by localized receptive fields, which may restrict modeling of long-range spatial relationships critical for complex tissue architectures. Vision Transformers (ViTs) offer an alternative paradigm based on self-attention, enabling global contextual reasoning across entire histopathological images. We evaluated a ViT-B/16 architecture for automated CRC classification using publicly available colorectal histopathology datasets. Methods: Digitized histopathological images from curated colorectal cancer datasets encompassing benign and malignant tissue classes were analyzed. Images underwent preprocessing including patch extraction, stain normalization, and data augmentation. Inputs were resized to 224×224 pixels and partitioned into non-overlapping 16×16 patches. A Vision Transformer B/16 architecture pretrained on ImageNet was fine-tuned for CRC classification. The model incorporated linear patch embeddings, positional encodings, a learnable class token, and 12 transformer encoder layers with multi-head self-attention. Data were split into training and validation cohorts with class balancing applied during training. Model performance was evaluated using accuracy, sensitivity, specificity, precision, recall, F1 score, and confusion matrix analysis. Results: The Vision Transformer achieved high classification performance, with sensitivity of 98% and specificity of 97% across colorectal tissue classes. Global attention-based feature modeling improved discrimination between morphologically similar regions and reduced misclassification in areas with complex glandular architecture or heterogeneous tumor–stroma interfaces. Overall performance was comparable to state-of-the-art CNN-based approaches, with the added benefit of improved global context modeling and enhanced interpretability through attention visualization. Conclusions: Vision Transformer–based modeling provides a robust and complementary approach for colorectal carcinoma histopathological classification by capturing long-range spatial dependencies beyond the capabilities of conventional CNNs. While computationally more intensive, ViT architectures offer unique advantages in modeling complex tissue organization and may serve as valuable components in next-generation AI-assisted diagnostic workflows for colorectal cancer.

Once unthinkable: Population-level changes in five-year survival for metastatic non–small cell lung cancer in the immunotherapy era.

e20696 Background: Five-year survival in metastatic non–small cell lung cancer (NSCLC) was historically rare. The introduction of immune checkpoint inhibitors has altered treatment paradigms, yet population-level evidence of long-term survival gains—and whether these gains extend across racial groups—remains limited. Methods: We performed a retrospective population-based cohort study using Surveillance, Epidemiology, and End Results (SEER) data to identify patients with de novo stage IV NSCLC diagnosed between 2010 and 2017. Five-year lung cancer–specific survival was estimated for non-Hispanic White (NHW) and non-Hispanic Black (NHB) patients using SEER*Stat. Temporal trends were analyzed using Joinpoint regression to assess changes over time. Results: Five-year survival for metastatic NSCLC nearly doubled during the study period, rising from approximately 6% in 2010 to 11–12% by 2017. Statistically significant annual improvements were observed in both non-Hispanic White (NHW) and non-Hispanic Black (NHB) populations. Survival trends remained parallel over time, with no statistically significant interaction between race and year of diagnosis (interaction p > 0.05). Conclusions: Population-level five-year survival for metastatic NSCLC has improved substantially in the immunotherapy era. Parallel survival gains among NHW and NHB patients suggest that advances in systemic therapy have translated into broadly shared long-term benefits. These findings support population health and policy efforts focused on equitable access to immunotherapy to sustain and extend survival gains nationwide.

Who receives CAR-T therapy? A national examination of racial and ethnic differences in hospitalized adults.

e18576 Background: CAR-T therapy has improved outcomes in hematologic malignancies but remains resource-intensive and largely confined to academic centers, raising concerns about equitable access. Given its distinctive toxicity profile, assessing real-world racial and ethnic disparities in CAR-T utilization and outcomes is essential. We evaluated racial and ethnic differences among hospitalized U.S. adults receiving CAR-T therapy using a nationally representative inpatient database, focusing on demographics, hospital utilization, treatment-related complications, and in-hospital outcomes. Methods: A retrospective cross-sectional study was conducted using the 2019–2023 National Inpatient Sample (NIS) database. Adult patients hospitalized (≥18 years) who received CAR-T therapy were identified using ICD-10 procedure codes. Patients were categorized by race/ethnicity as white, black, and hispanic, and outcomes were compared across groups. Univariable and multivariable logistic regression was performed to evaluate associations between race/ethnicity and mortality, age, gender, length of stay, hospital cost, and clinical outcomes. Results: Among 10,690 hospitalized adult CAR-T recipients, most were male (61%), privately insured (47%), treated at large (75%) and teaching hospitals (99%). Most recipients were White (74%), followed by Hispanic (11%) and Black (7%). Compared to White recipients, Black (mean age 58 years; Coef −2.9; P<0.05) and Hispanic recipients (Coef −12.5; P<0.001) were younger, while White patients were older (Coef 3.7; P<0.001). Hispanic patients had longer length of stay than White patients (19.1 vs 16.9 days; Coef 2.1; P<0.05). After multivariable adjustment, Black patients had increased cardiovascular complications (OR 1.8; P<0.05), whereas Hispanic patients had lower odds (12% vs 25%; OR 0.40; P<0.001). CRS (34% vs 47%; OR 0.57; P<0.001) and ICANS (4% vs 14%; OR 0.25; P<0.001) were lower in Hispanic than White patients, while TLS was more common in Hispanic patients (9% vs 5%; OR 2.0; P<0.05). No racial differences were observed in in-hospital mortality, sex distribution, or hospital costs. Conclusions: This study highlights significant racial and ethnic heterogeneity exists in CAR-T–associated toxicities despite similar in-hospital mortality and costs. These findings suggest differences in comorbidity burden, disease biology, or care delivery processes. Prospective studies should prioritize equity-focused risk stratification, standardized toxicity monitoring, and longitudinal outcomes to mitigate disparities in CAR-T care.

Convergent Total Synthesis of 16β‐Hydroxylpseudobufarenogin

ABSTRACT 16β‐Hydroxylpseudobufarenogin ( 1 ), isolated from the venom of Bufo bufo gargarizans , has potent anticancer activity. The U‐shaped steroidal structure of 1 possesses a cis ‐fused AB‐ring system, a densely oxidized cis ‐fused CD‐ring system, and a β‐oriented 2‐pyrone at C17. Herein, we present a new convergent strategy for assembling this complex steroidal architecture, culminating in the first total synthesis of 1 in 28 steps from (+)‐Wieland–Miescher ketone. The AB‐ and D‐ring fragments were coupled by Pd/Ag‐promoted Suzuki–Miyaura coupling. Following the Co‐catalyzed hydration of the D‐ring, the C‐ring was stereoselectively constructed by Ir‐catalyzed radical‐relay cyclization. Subsequent C‐ring hydroxylation and installation of the β‐oriented 2‐pyrone through Pd/Cu‐promoted Stille coupling and stereospecific epoxide rearrangement delivered 1 . Because of its high chemo‐ and stereoselectivity, the present methodology would be applicable to the total synthesis of diverse oxygenated bufadienolides by simply altering the fragment structures.

Structural, optical and gas sensing studies for high-performance chlorine gas sensor based on hydrothermally synthesized CuFe2O4/CuO nanocomposite

Neoadjuvant GOLP is effective in high-risk intrahepatic cholangiocarcinoma