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Cancer cachexia and symptomatic toxicity among 706 older adults with advanced cancer receiving treatment: A URCC NCORP nationwide study.

12067 Background: Cancer cachexia is a severe wasting condition characterized by rapid weight loss. Its impact on symptomatic toxicity is poorly defined in geriatric oncology populations, who are at high risk for cachexia. Symptomatic toxicity is central to treatment tolerability and is linked to poor quality of life, functional decline, and reduced survival. We evaluated whether cachexia is associated with symptomatic toxicity before and during high-risk cancer treatment in older adults with advanced cancer. Methods: In a randomized controlled trial (GAP70+; NCT02054741), adults aged ≥70 with stage III or IV solid tumors or lymphoma were recruited prior to starting a new cancer treatment from 40 community oncology practices affiliated with the University of Rochester NCI Community Oncology Research Program (NCORP) Research Base. Cachexia (≥5% weight loss in the past six months) was assessed at baseline via Mini Nutritional Assessment. Symptoms (fatigue, insomnia, pain, anorexia, dyspnea, concentration problems, nausea, sensory neuropathy, constipation, diarrhea) were assessed at baseline and 3 months using the Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE). Symptoms were measured as mild, moderate, severe, or very severe. Log-binomial regression models examined associations of cachexia with baseline and three-month incident symptoms (baseline-adjusted method). Results: Among 706 participants (mean age: 77.2 years; 57% male; 59% gastrointestinal or lung cancer; 26% received prior chemotherapy), 42% had cachexia at baseline. Participants with cachexia were more likely than those without to report severe/very severe baseline symptoms (56% vs. 35%, chi-square p < 0.01). Analyses show that those with cachexia were 2-3 times more likely to report baseline severe/very severe anorexia (Risk Ratio (RR): 3.64, 95%CI: 2.44 - 5.42), fatigue (RR: 2.28, 95%CI: 1.65 - 3.16), pain (RR: 2.03, 95%CI: 1.36 - 3.04), and constipation (RR: 2.02, 95%CI: 1.27 - 3.22), as well as moderate or worse nausea (RR: 1.72, 95%CI: 1.16 - 2.55) and concentration problems (RR: 1.56, 95%CI: 1.03 - 2.39; all p < 0.05). Baseline cachexia was also associated with the development of severe/very severe anorexia (RR: 1.88, 95%CI: 1.20 - 2.94; p < 0.01) from baseline to 3-months. Conclusions: Nearly half of older adults with advanced cancer initiating a treatment regimen have cachexia. We demonstrate via PRO-CTCAE that cachexia is associated with a significantly worse pre-treatment symptom burden. Cachexia was linked to severe anorexia before and after treatment initiation, highlighting a critical gap in supportive care. As novel agents targeting appetite and cachexia enter phase III trials, further research is needed to establish the temporal course of cachexia-related symptoms to identify ideal timing and candidates for therapeutic strategies. Clinical trial information: NCT02054741 .

Neoadjuvant serplulimab plus nab-paclitaxel and SOX in locally advanced gastric or gastroesophageal junction adenocarcinoma: An interim analysis of a multicenter, randomized, double-blind, phase II trial.

e16131 Background: Despite standard neoadjuvant chemotherapy and radical resection, patients with locally advanced gastric cancer (GC) face a high risk of recurrence and poor long-term survival. Although intensified chemotherapy with nab-paclitaxel plus SOX has shown improved tumor regression, pathological responses remain limited. Whether adding immunotherapy can further enhance pathological benefit while preserving surgical feasibility remains unclear. This trial evaluated the efficacy and safety of serplulimab, a PD-1 inhibitor, combined with nab-paclitaxel and SOX as neoadjuvant therapy under close safety monitoring. Methods: This multicenter, randomized, double-blind controlled trial enrolled patients with pathologically confirmed locally advanced GC or gastroesophageal junction (GEJ) adenocarcinoma and an ECOG performance status of 0-1. Patients were assessed by a multidisciplinary team as having potential for R0 resection, but upfront surgery was deemed technically challenging. Patients were randomized to receive 3 cycles of neoadjuvant serplulimab plus nab-paclitaxel and SOX (immunochemotherapy) or placebo plus nab-paclitaxel and SOX (chemotherapy), followed by curative-intent gastrectomy with D2 lymphadenectomy. The primary endpoints were pathological complete response (pCR) and safety. Secondary endpoints included major pathological response (MPR), R0 resection rate. Results: A total of 98 patients were screened, and 51 eligible patients (median age, 62 years) were enrolled and randomized to the immunochemotherapy (n = 23) or chemotherapy (n = 28) group. All patients received surgery after neoadjuvant. The pCR rate was significantly higher in the immunochemotherapy group than in the chemotherapy group (30.4% vs 3.6%; P = 0.025), as was the numerically higher MPR rate (39.1% vs 17.9%; P = 0.090). The R0 resection rate was comparable between the two groups (100.0% vs. 92.9%), while a significantly higher rate of postoperative N downstaging was observed in the immunochemotherapy group (78.3% vs 46.4%; P = 0.021). The incidence of grade 3-4 adverse events (AEs) was 19.6% (n = 10), with a comparable safety profile between the two groups. No grade 5 toxicity was observed. Crucially, AEs were manageable and did not delay neoadjuvant treatment or postponement of surgery in either group. Conclusions: Neoadjuvant serplulimab combined with an intensified regimen of nab-paclitaxel and SOX showed promising efficacy in fit patients with locally advanced GC/GEJ adenocarcinoma. This strategy significantly improved pCR rates and promoted nodal downstaging, with a safety profile that did not compromise surgical feasibility. The study is ongoing; long-term follow-up and exploratory analyses are required to further evaluate the durability and full potential of this strategy. Clinical trial information: NCT06576921 .

Lymph node ratio and patterns of recurrence in oral squamous cell carcinoma treated with surgery and adjuvant concurrent chemoradiotherapy.

e18084 Background: Despite curative surgery and adjuvant concurrent chemoradiotherapy (CCRT), a subset of patients with oral squamous cell carcinoma (OSCC) develop disease recurrence. Conventional nodal staging may not adequately reflect postoperative nodal burden or residual risk. Lymph node ratio (LNR), defined as the proportion of metastatic to examined lymph nodes, may better characterize recurrence patterns following standard multimodality treatment. Methods: This retrospective clinical study evaluated 1,783 patients with OSCC treated with surgery and adjuvant CCRT between 2019 and 2023. Patients who developed recurrence during follow-up and had complete pathological and clinical data were analyzed (n=119; 6.7%). LNR was calculated as the number of positive lymph nodes divided by total nodes retrieved and categorized as ≤0.10 or >0.10. Recurrence pattern and time to recurrence were assessed. Results: Median lymph nodes retrieved was 29 (range 17–39), with a median of 1 positive node (range 1–9). Median LNR was 0.05 (range 0.02–0.52); 89 patients (74.8%) had LNR ≤0.10 and 30 (25.2%) had LNR >0.10. Recurrence was predominantly locoregional, occurring in 108 patients (90.8%), while distant recurrence occurred in 9 patients (7.6%) and combined locoregional and distant failure in 1 patient (0.8%). Median time to recurrence was 19 months. A higher LNR was associated with a greater proportion of non-locoregional failure. Conclusions: In a large, uniformly treated OSCC cohort, recurrence after surgery and adjuvant CCRT is infrequent but overwhelmingly locoregional. Postoperative lymph node ratio provides a pragmatic measure of nodal burden and identifies patients with a higher likelihood of non-locoregional failure despite standard therapy. LNR may complement conventional nodal staging to inform post-treatment risk stratification and surveillance strategies. Clinicopathologic characteristics and recurrence patterns by lymph node ratio (LNR). Variable Overall (n = 119) LNR ≤0.10 (n = 89) LNR >0.10 (n = 30) Median lymph nodes retrieved, n (range) 29 (17–39) 28 (17–39) 31 (18–38) Median positive lymph nodes, n (range) 1 (1–9) 1 (1–3) 4 (2–9) Median LNR (range) 0.05 (0.02–0.52) 0.04 (0.02–0.10) 0.21 (0.11–0.52) Locoregional recurrence, n (%) 108 (90.8) 83 (93.3) 25 (83.3) Distant recurrence, n (%) 9 (7.6) 5 (5.6) 4 (13.3) Combined locoregional + distant recurrence, n (%) 1 (0.8) 0 1 (3.3) Median time to recurrence, months 19 21 14

Treatment patterns and outcomes with olutasidenib after venetoclax in IDH1-mutated AML using real-world data from a chart review.

e18527 Background: Olutasidenib (OLU), a selective oral inhibitor of mutant IDH1 (m IDH1 ), is a key treatment option for patients with m IDH1 mutated acute myeloid leukemia (AML). Targeted agents are used for patients following failure of chemotherapy or front-line venetoclax (VEN)-based regimens. OLU is approved for relapsed/refractory (R/R) m IDH1 AML. In the pivotal Phase 2 trial (NCT02719574), OLU achieved CR/CRh in 35% of patients, with a median duration of CR/CRh of 25.3 months and acceptable tolerability; however, real-world data on OLU utilization and outcomes post-VEN remain limited. Methods: This retrospective cohort study used data from a physician-based chart review. Eligible patients were ≥18 years old and had R/R AML with an IDH1 mutation, prior treatment with VEN, initiated OLU between December 2022 – March 2025, and were assessed for a response. Patients were excluded if they received prior IDH1 targeted therapy or >1 additional therapy between receipt of VEN and OLU. Patient disease characteristics, prior treatment history, and effectiveness and safety outcomes were summarized using descriptive statistics. Duration of response was estimated using Kaplan-Meier (KM) methods. Results: Fifty-one charts were collected from 18 physicians. The median patient age at diagnosis was 61 years and 78% were male. The median follow-up time from diagnosis was 23.6 months. ECOG was 0-1 in 54.9% and 2-3 in 45.1% of patients at time of OLU initiation and 15.7% had AML with antecedent MDS. Most patients (60.8%) harbored at least one co-mutation, the most common being DNMT3A (43.1%), FLT3 (35.3%) and NPM1 (35.3%). Most patients (90.2%) received VEN-based therapy in the first-line; overall, ORR was 81.3% and a CR/CRi of 47.9%. The median duration of prior VEN treatment was 4.2 months (IQR, 1.6-16.2 months). OLU was mostly given as monotherapy (96.1%) and in the second line (72.5%), with 27.5% given as third-line treatment. Median OLU treatment duration was 12.6 months (IQR, 7.2-20.1 months). The ORR for OLU was 90.2%, with 60.8% CR/CRh and 57% CR, with a median CR/CRh DOR of 30.3 months. Of the 36 (70.6%) patients who were RBC and/or platelet transfusion dependent at baseline, 20 (55.6%) achieved transfusions independence while on OLU. Of the 12 patients discontinuing OLU, the primary reason was disease progression (41.7%). The most common adverse events were fatigue (11.8%), infection, neutropenia, and nausea (each 7.8%). Conclusions: OLU demonstrated robust real-world effectiveness in adults with R/R m IDH1 AML previously treated with VEN, a subgroup that historically has very poor outcomes, with a CR/CRh rate of 60.8% and a median response duration of 30.3 months. Substantial reductions in transfusion dependence further support OLU as a viable post-VEN therapeutic option. These findings suggest that earlier sequencing of OLU in the treatment paradigm may optimize patient outcomes.

Beamion BCGC-1: Four new phase Ib/II cohorts to evaluate oral zongertinib with other agents in HER2-positive metastatic breast cancer (mBC) and metastatic colorectal cancer (mCRC).

TPS3177 Background: Zongertinib, an oral, irreversible TKI, selectively inhibits HER2 while sparing wild-type EGFR, thereby minimizing associated toxicities. Beamion BCGC-1 (NCT06324357) is an ongoing Phase (Ph) Ib/II trial evaluating zongertinib in HER2-positive tumors. Trial details for Cohorts A–K, evaluating zongertinib as monotherapy or combined with T-DM1, T-DXd, or trastuzumab ± capecitabine in patients (pts) with HER2-positive mBC, and with T-DXd in pts with HER2-positive metastatic gastric, gastroesophageal junction, or esophageal adenocarcinoma (mGEAC), have recently been published (Hurvitz et al, Future Oncol 2025). In addition to BC and GEAC, early-phase data indicate zongertinib is also active in mCRC (Yoh et al, Ann Oncol 2025, abstr 491P). Here, we report 4 new cohorts (L–O) to evaluate the efficacy and safety of zongertinib plus zanidatamab in HER2-positive mBC, or plus trastuzumab or mFOLFOX6 ± trastuzumab in HER2-positive mCRC. Methods: For the 4 new cohorts, pts must have histologically/cytologically confirmed, unresectable HER2-positive mBC or mCRC, and documented HER2-positive disease (overexpression/amplification). Pts with mBC must have disease progression following ≥1 prior HER2-targeted treatment; pts with mCRC must have disease progression/recurrence during or following their latest treatment. Pts with brain metastases are allowed. There are 3 new Ph Ib cohorts (M, N, and O; each ~20 pts). Cohorts M and N will assess zongertinib in mCRC: pts will receive once-daily zongertinib across escalating dose levels plus mFOLFOX6 every 14 days (Cohort M), or mFOLFOX6 every 14 days + trastuzumab every 21 days (Cohort N; Table). In Cohort O, pts with mBC will receive once-daily zongertinib across escalating dose levels plus zanidatamab every 21 days. Dose escalation will be guided by a BLRM with overdose control. In Ph II, Cohort L, a new dose justification cohort (~40 pts with mCRC), will receive zongertinib 120 mg once daily plus trastuzumab every 21 days. In Ph Ib, the primary endpoint is DLTs during the MTD evaluation period; secondary endpoints include objective response (OR) by RECIST v1.1, DLTs in the on-treatment period, and pharmacokinetics (PK). In Ph II, the primary endpoint is OR by RECIST v1.1; secondary endpoints include PFS, disease control, AEs leading to dose reduction, PK, and pt-reported outcomes. Pts will remain on treatment until any protocol-defined stopping criterion occurs. Clinical trial information: NCT06324357 . Cohort Indication Zongertinib Regimen Ph Ib dose escalation M mCRC + mFOLFOX6: oxaliplatin (85 mg/m 2 ), leucovorin (400 mg/m 2 ), 5-FU (2400 mg/m 2 ) N mCRC + mFOLFOX6: oxaliplatin (85 mg/m 2 ), leucovorin (400 mg/m 2 ), 5-FU (2400 mg/m 2 ) + trastuzumab (8 mg/kg loading; 6 mg/kg maintenance) O mBC + zanidatamab (1800 mg <70 kg; 2400 mg ≥70 kg) Ph II dose justification L mCRC + trastuzumab (8 mg/kg loading; 6 mg/kg maintenance)

Contribution of atezolizumab (atezo) to the efficacy of the zanzalintinib (zanza) + atezo combination in patients (pts) with previously treated metastatic colorectal cancer (mCRC): Evidence from the phase 3 STELLAR-303 trial.

3574 Background: Outcomes remain poor for pts with previously treated mCRC, the vast majority of whom have tumors that are not microsatellite instability-high or mismatch repair deficient. Zanza is a novel, small molecule inhibitor of multiple kinases, including TAM kinases (TYRO3, AXL, and MER), MET, and VEGF receptors, which play important roles in oncogenic processes, including immune suppression in the tumor microenvironment. In STELLAR-303, zanza + atezo significantly improved overall survival (OS) versus regorafenib (rego) in pts with previously treated mCRC. The objective here was to assess the contribution of atezo to the efficacy of the zanza + atezo combination. Methods: The effect of atezo immunogenicity on efficacy was evaluated by comparing progression-free survival (PFS) and OS between atezo treatment-emergent anti-drug antibody (TEADA)-positive and TEADA-negative pts. Unstratified Cox proportional hazards regression models were used to estimate HRs for TEADA subgroups relative to the rego arm. Exposure-response (ER) analyses examined the relationship between atezo serum trough concentrations and efficacy endpoints using Cox proportional hazards models. Results: Of 451 pts randomized to zanza + atezo, 394 were evaluable for atezo TEADAs (TEADA-positive at any post-baseline visit, n = 143; TEADA-negative, n = 251). Baseline clinical characteristics and key prognostic factors (eg, RAS status, geographic region, presence of liver metastasis, location of primary tumor) were well balanced between TEADA subgroups, minimizing potential confounding due to subpopulation differences. Relative to the rego arm (n = 450), HRs (95% CI) favored zanza + atezo for PFS across both TEADA-positive (0.81 [0.67–0.99]) and TEADA-negative (0.59 [0.51–0.71]) subgroups. Similar results were observed for OS in the TEADA-positive (0.79 [0.63–0.98]) and TEADA-negative (0.72 [0.60–0.86]) subgroups. The greatest benefit for both PFS and OS was in the TEADA-negative subgroup. Based on ER analyses (n = 376), there was a statistically significant (p < 0.001) relationship between time-varying atezo trough concentrations and efficacy endpoints—estimated HRs (95% CI) comparing the 95 th with the 5 th percentiles of atezo trough concentrations were 0.82 (0.80–0.83) for PFS and 0.73 (0.70–0.75) for OS. Safety profiles were comparable between TEADA-positive and TEADA-negative pts. Conclusions: Zanza + atezo demonstrated PFS and OS benefit regardless of atezo TEADA status, with greater efficacy observed in TEADA-negative pts. ER analyses showed that higher atezo serum trough concentrations were associated with longer PFS and OS. These results support the contribution of atezo to the survival benefits observed with the zanza + atezo combination in pts with mCRC in the STELLAR-303 trial. Clinical trial information: NCT05425940 .

Toxicity risk calculator for personalised prediction of irAEs in patients with solid tumours receiving ICIs, developed based on a clinical dataset and machine learning approaches.

1628 Background: Immune checkpoint inhibitors (ICIs) can cause severe (grade 3-4) immune-related adverse events (irAEs), which complicate treatment and require immunosuppressive therapy. To address this, we developed a machine learning (ML)-based tool to predict individual risk. Aim: To identify predictors and develop an ML calculator for assessing the risk of grade 3–4 irAEs in patients receiving ICIs for solid tumours. Methods: This retrospective study included 1,001 patients (585 men, 415 women; mean age 62.4) treated with ICIs for melanoma, kidney, lung, GI, or cervical cancers. The workflow was implemented in Python using pandas, scikit-learn, and SHAP. The cohort was split 70/30 for training and testing. Only pre-treatment variables were used. Data preprocessing included imputation (median for numeric, most frequent for categorical), one-hot encoding, and standardization. Two classifiers were trained: elastic-net logistic regression and gradient boosting. Hyperparameters were tuned via 5-fold CV. Class imbalance (~7-8% positives) was addressed with class_weight="balanced" and SMOTE. Probabilities were calibrated. Performance was assessed by PR-AUC (primary), ROC-AUC, F1, and Brier score. Predictors were selected in a two-stage process: 1) Retention of pre-IO variables, removal of low-variance/high-missingness (>30%) features, and collinearity pruning (|correlation| > 0.85). 2) Model-agnostic ranking using three normalized signals: elastic-net coefficients, permutation importance, and mean absolute SHAP values, combined into a consensus score (weights: 0.5, 0.3, 0.2). Stability was verified by bootstrap resampling. Results: The final 10 features maximized cross-validated PR-AUC while maintaining calibration and interpretability. Selected predictors: ICI type/combination; age; haemoglobin; creatinine; treatment regimen (mono/combo); K-RAS/N-RAS mutation status; skeletal muscle index; lymphocyte-to-monocyte ratio; immunotherapy line; T4 level.The model identifies patients at increased risk with calibrated probabilities. Results are presented as probabilities (95% CI) categorized as low (<0.10), moderate (0.10–0.25), and high (≥0.25). The colored pictogram visualizes risk distribution for a sample of 100 patients (based on the database; median, quartiles). Conclusions: We developed the 'Toxicity Risk Calculator' using 10 clinical factors to assess the probability of severe irAEs. This calculator enables routine assessment of the low, moderate, or high probability of grade 3–4 irAEs, facilitating more effective personalization of cancer immunotherapy in everyday practice. Further prospective studies in real-world clinical settings are needed.

Impact of oral SERDs, including giredestrant, on survival in HR+ HER2− metastatic breast cancer: A meta-analysis.

1084 Background: Oral selective estrogen receptor degraders (SERDs) are designed to overcome endocrine resistance in HR+ HER2- breast cancer due to ESR1 mutations. Several SERDs have been evaluated in recent trials. We performed a meta-analysis evaluating oral SERDs in previously treated patients with HR+ HER2- metastatic breast cancer (MBC). Methods: Randomized controlled trials comparing oral SERDs to standard endocrine therapy in previously treated HR+, HER2- MBC, reporting progression-free survival (PFS) or overall survival (OS) and adverse events (AEs), were identified via a systematic PubMed search. To incorporate the latest SERDs data, results from the recently presented giradestrant trial were included. Meta-analysis was performed for the overall intention-to-treat (ITT) population and the ESR1-mutant (ESR1m) subgroups. Leave-one-out analyses excluding giradestrant were conducted to highlight its specific impact. Rates of serious adverse events (grade ≥3) and treatment discontinuation were also analyzed. Results: A total of 2324 patients from six phase III trials were included in this analysis. Oral SERDs improved PFS compared with standard endocrine therapy in the ITT population (HR 0.734, CI 0.620-0.869, p<0.001) with greater benefit observed in the ESR1m subgroup (HR 0.538, CI 0.430-0.673, p<0.001). Excluding giradestrant data from the evERA trial led to modest reduction in PFS benefit in both the ITT (HR 0.755, CI 0.661-0.908, p<0.05) and the ESR1m (HR 0.582, CI 0.471-0.718, p<0.05) subsets, though overall PFS benefit remained. Additionally, SERDs were associated with an OS advantage in pooled analyses for the ITT population (HR 0.743, CI 0.621-0.889, p<0.05) and ESR1m population (HR 0.584, CI 0.433-0.768, p<0.001). Excluding giradestrant did not result in significant changes in OS estimates. Grade ≥3 AEs were more frequent with SERDs (OR 1.53, CI 1.20-1.95, p<0.001) while discontinuation rates were similar between groups (OR 1.53, CI 0.99-2.37, p=0.06). Conclusions: Oral SERDs significantly improve PFS in previously treated HR+ HER2- MBC with the greatest benefit in patients with ESR1 mutations. Pooled analysis suggests an OS advantage favoring SERDs. Giradestrant contributes to the observed PFS class effect without altering OS outcomes. SERDs are associated with increased toxicity. Although a trend towards higher discontinuation rates was noted, it did not reach statistical significance, and discontinuation rates remain comparable to standard endocrine therapy. These findings support the use of oral SERDs in the second- and third-line treatment of HR+ HER2- MBC, particularly in ESR1-mutant disease.

Stage gap and projected metastatic surge for young-onset colorectal cancer: A decade-long call to action.

e15702 Background: By 2023,1 in 10 colon cancers and 1 in 4 rectal cancers will occur under age 50. Young-onset colorectal cancer (YOCRC) often presents at advanced stages (stage III and IV) and is the leading cause of cancer death under age 50. To inform strategies for mitigating disease burden in the decade ahead, we aimed to estimate the projected 5-year (by 2027) and 10-year (by 2032) trends in stage distribution of YOCRC. Methods: Data from patients diagnosed with histologically confirmed colon or rectal cancer from 2004 through 2022 were queried from the Surveillance, Epidemiology, and End Results (SEER) 21 cancer registry. The age-adjusted incidence rate (per 100,000 population) was calculated and stratified by age at diagnosis (young onset [YO]: 18-49 years, vs. later-onset [LO]: 50+ years), stage (local, regional, distant) and location (colon versus rectosigmoid and rectum). Annual percentage changes (APCs) and p-values of trends were determined using SEER*Stat software. The predicted incidence rates were calculated using estimated APCs assumed to change at a constant percentage of the previous year’s rate. Projected percent change was reported relative to 2022 incidence rates. Results: Among 816,417 patients, 99,951 (12.2%) had YO and 716,466 (87.8%), LO disease. Relative to 2022, the incidence of metastatic disease among YO patients is projected to increase by 13.5% in 5 years (2027) and 28.8% in 10 years (2032). Similarly, regionally advanced disease is projected rise by 10.9% and 23.0% at 5- and 10 years, respectively. Localized disease is projected to remain stable overall. In contrast, among LO patients, incidence is projected to decline across all stages by 2027 (localized −19.5%, regional −11.1%, distant −7.1%) and further by 2032 (localized −35.2%, regional −21.0%, distant −13.8%). Most alarmingly, site-specific analyses for YO patients projected to 2032 highlight pronounced increases in metastatic (+47.7%) and in regionally advanced (+44.5%) rectal cancer cases, followed by that of metastatic (+23.3%) and regional-advanced (+14.6%) colon cancers. Localized disease is expected to remain largely stable for colon cancer, with a slight decline for rectal cancer (−2.1% by 2027; −4.2% by 2032). Projected over the same decade, for LO adults, the largest declines are expected in incidences of localized colon (-20% by 2027; - 36.0% by 2032) and localized rectal (-17.7% by 2027; -32.3% by 2032) cancers. Conclusions: A significant age-based divergence in the trajectory of regionally advanced and metastatic CRC incidence is projected over the next decade. Within the next decade, 1 in 5 advanced-stage diagnoses of CRC will occur in young adults under age 50, with the largest increases seen in metastatic and locally advanced rectal cancers. These data highlight the urgency for implementing screening and treatment interventions.

Does treatment sequencing matter in stage IV NSCLC with brain metastases? A National Cancer Database study.

e20657 Background: The optimal sequencing of brain-directed radiation and systemic therapy in stage IV NSCLC with brain metastases remains unclear. We evaluated survival outcomes associated with treatment sequencing using NCDB across contemporary treatment eras. Methods: Adult patients (2010–2022) with stage IV NSCLC and brain metastases at diagnosis who received both brain radiation and systemic therapy were identified from the NCDB. Treatment sequence was defined by initiation order (radiation-first vs systemic-first); patients with same-day initiation or upfront surgery were excluded. Overall survival (OS) was assessed using Kaplan–Meier and multivariable Cox models stratified by diagnosis era (pre-2015 vs ≥2015). Immortal time bias was addressed using a delayed-entry sensitivity analysis. Temporal trends were evaluated with logistic regression. Results: Among 45,577 patients, 35,706 (78.3%) received radiation-first and 9,871 (21.7%) systemic-first therapy. In unadjusted analyses, OS did not differ between sequences (log-rank p=0.055). By era, no difference was observed pre-2015 (p=0.56), while systemic-first therapy was associated with improved unadjusted OS in patients diagnosed in 2015 or later (p=0.018). After multivariable adjustment, OS was comparable between sequences (aHR 1.03 [0.98–1.09]). Delayed-entry sensitivity analyses showed a small increase in hazard with systemic-first approach (aHR 1.07 [1.01–1.13]). Older age, higher comorbidity burden, Hispanic and Asian race, Medicaid insurance, and longer time to treatment initiation were associated with increased mortality. Use of systemic-first therapy increased over time (aOR per year 1.03 [1.02–1.04]). Conclusions: In this national cohort of patients with brain-metastatic NSCLC receiving multimodal therapy, OS was similar between radiation-first and systemic-first sequencing after adjustment. These findings suggest that, in appropriately selected patients, initiating systemic therapy before brain radiation may be reasonable without OS compromise, supporting individualized sequencing decisions. Temporal shifts toward systemic-first strategies likely reflect evolving practice patterns rather than a survival advantage. Variable Category aHR (95% CI) Variable Category aHR (95% CI) Treatment sequence (ref: radiation-first) Systemic-first 1.03(0.98,1.09) CCI (ref:0) 1 1.10 (1.04,1.17) Age group (ref: ≤64 years) ≥65 years 1.16 (1.08,1.24) 2 1.11 (1.00,1.23) Sex (ref: Male) Female 0.98 (0.94,1.03) ≥3 1.24 (1.09,1.42) Race (ref: NH White) Hispanic 1.35 (1.21,1.51) Histology (ref: Adenocarcinoma) SCC 1.10 (1.00,1.20) Black 1.06 (0.99,1.13) NSCLC NOS 0.78 (0.71,0.86) Asian 1.14 (1.04,1.25) Time from diagnosis to treatment 1.003 (1.002,1.003) Insurance (ref: Private insurance) Medicaid 1.15 (1.07,1.25) Medicare 1.01 (0.94,1.09) Self-pay 1.19 (1.06,1.35)

Acceptability of a narrative video intervention to promote clinical trial decision-making among Black women with breast cancer.

e23192 Background: Black women are more likely to present with advanced stage disease and to die following a breast cancer (BC) diagnosis compared with women from other racial and ethnic groups. This persistent health inequity is in part driven by underrepresentation in clinical trials (CTs), as well as structural and social drivers of health. The overall objective of this study is to pilot-test a narrative decision aid designed to support CT decision-making among Black breast cancer patients receiving care in safety-net oncology settings. Here, we report comparative outcomes from an acceptability study conducted at two safety-net oncology practices among end-users. Methods: We conducted a pre/post-intervention survey study at two safety-net oncology centers in Chicago, Illinois. Black women with a diagnosis of BC (any stage, any point during treatment or follow-up) were identified by their oncologist and invited to participate. Consenting participants completed a pre-survey, viewed the video intervention on an electronic device, and completed a post-survey. The survey included items related to demographics, prior exposure to CTs, CT knowledge, self-efficacy, and video acceptability. We calculated descriptive statistics (mean, standard deviation) for pre- and post-intervention scores and used paired t-tests to analyze the change in scores from pre- to post-intervention. We defined prior CT exposure as self-reporting ever being invited to participate and/or participating in a CT. Results: Thirty patients participated. Across both sites, 19 patients reported prior CT exposure. Among all participants, the mean CT knowledge score numerically increased from 83.8% at baseline to 86.7% post-viewing (p = 0.4). Across 11 items assessing self-efficacy regarding decision-making about CTs, mean scores rose for all participants from 3.41 to 3.59 (p = 0.008). After viewing the video, in regards to the statement “I feel confident I can understand the information enough to be able to make a choice about participating in CTs,” self-rated efficacy scores numerically rose from 68.4% to 84.2% (p = .08) for those CT-exposed and from 45.5% to 81.8% (p = .052) for those CT non-exposed. The video was highly acceptable: 100% of participants previously exposed and 91% of participants not previously exposed indicated they were extremely or somewhat likely to share it with family or friends. Conclusions: This study demonstrated that a culturally tailored, narrative-based video intervention is acceptable to Black breast cancer patients and is associated with numerical improvements in CT knowledge as well as decision-making self-efficacy, regardless of previous CT exposure or clinic site. These findings support the feasibility of implementing such interventions across diverse safety-net oncology settings and indicate a call to further test this intervention on a larger scale.

Study on the pathogenesis of PLXNB1 gene in olfactory dysfunction of allergic rhinitis

Background Olfactory dysfunction (OD) is a common yet underrecognized symptom of allergic rhinitis (AR). While inflammation contributes to OD, the underlying molecular mechanisms remain unclear. Methods Differential gene expression analysis was conducted using GEO datasets (GSE75011 and GSE43523). OD DEGs were identified and used to construct a protein-protein interaction (PPI) network. Key genes were filtered through LASSO regression and validated through immune infiltration analysis. The biological function of PLXNB1 was further investigated via in vitro human nasal epithelial cell models and an in vivo mouse model of AR. Results PLXNB1 expression was significantly downregulated in AR patients compared to healthy controls in both training and validation datasets. Immune infiltration analysis revealed a negative correlation between PLXNB1 and pro-inflammatory immune cells. Functional assays showed that PLXNB1 knockdown led to increased expression of inflammatory cytokines (e.g., IL-4, IL-6), likely via activation of the MAPK/p38 signaling pathway. Conversely, overexpression or Desloratadine treatment restored PLXNB1 levels and suppressed inflammation. Conclusion PLXNB1 is a potential hub gene linking immune dysregulation to olfactory dysfunction in AR. Its downregulation exacerbates inflammation and may impair olfactory function via the MAPK/p38 axis. These findings offer new insights into AR pathogenesis and identify PLXNB1 as a promising target for therapeutic intervention.

Persistence of self-limited conditions in bulk silicon induced by mid-infrared femtosecond laser pulses

With the advent of intense infrared laser solutions, three-dimensional laser writing progressively becomes applicable to silicon (Si) and other semiconductors. However, the nonlinearities required for bulk-energy deposition also induce severe beam distortions, causing processing difficulties in the short-wave infrared domain. Here, we assess the potential of longer wavelengths in the mid-infrared (MIR) domain by systematically comparing microplasma formation and material modification in Si using sub-200-fs pulses at 1.4 and 4 μm. Under identical tight-focusing conditions, both wavelengths generate well-defined plasmas with similar maximum densities at ≈1020 cm−3. Z-scan writing experiments exploring energies exceeding the observed ionization limit show that neither wavelength enables internal structuring of Si, in contrast to temporally stretched picosecond pulses. While ionization dynamics and characteristics can be varied significantly with wavelength, we show that pronounced filamentary effects restrict the potentially expected advantages of the MIR domain for ultrafast laser internal structuring of semiconductors.

The influence of ion beam-synthesized InSb nanocrystals on current-voltage characteristics of SiO2 layers in MOS structures

A Robust Biopolymer Network Binder for High‐Loading Iodine Cathodes in Zinc‐Iodine Batteries

ABSTRACT High energy density and long cycle life are critical for practical aqueous zinc‐iodine batteries (AZIBs). However, the development of high‐mass‐loading iodine cathodes faces bottlenecks, such as structural instability, severe polyiodide shuttling, and sluggish charge transfer kinetics. Herein, a robust biopolymer network (XGP) binder is developed, featuring a 3D network structure with dense hydrogen bonding that provides strong adhesion and good mechanical strength for high‐mass‐loading active carbon (AC)@I 2 cathodes. Using a scalable slurry‐drawing method, the obtained thick AC@I 2 electrodes exhibit a porous architecture with high porosity (47.6%), facilitating rapid Zn 2 + diffusion (up to 10 −9 cm 2 s −1 ) and fast electrochemical kinetics. Furthermore, diverse oxygen functional groups in the XGP binder provide strong chemical anchoring sites, effectively suppressing polyiodide shuttling. Consequently, XGP‐based cathodes with an ultrahigh iodine loading (82 mg cm −2 , ∼960 µm) achieve an areal capacity of 15.3 mAh cm −2 . Zn‐I 2 pouch cells deliver a capacity of 1744 mAh over 600 cycles, yielding a remarkable energy density of 55.0 Wh L −1 at the cell level. This work solves key challenges in thick iodine electrodes through integrated design of the biopolymer binder and electrode engineering, paving the way for practical AZIBs.

Detection of Mycobacterium tuberculosis antigens in urinary extracellular vesicles using real-time immuno-PCR: A non-invasive diagnostic approach for pulmonary tuberculosis

Calcium-loaded acylated segment controls membrane penetration capacity of repeats-in-toxin cytolysins

Safety and feasibility of intratumoral injection of RP1 or RP2 oncolytic immunotherapies in visceral metastases.

2597 Background: RPx is an investigational HSV-1-based oncolytic immunotherapy platform including RP1 (vusolimogene oderparepvec) and RP2. RP1 expresses GM-CSF and a fusogenic glycoprotein (GALV-GP-R – ); RP2 also expresses an anti–CTLA-4 antibody-like molecule. We report safety data from patients (pts) who received intratumoral (IT) injections of RP1/2 into visceral metastases (mets). Methods: Pts with advanced/metastatic solid tumors were enrolled into RP1/2 clinical trials (RP1: NCT03767348; RP2: NCT04336241). RP1/2 was injected into visceral tumors using CT or ultrasound guidance. The recommended needle gauges ranged from 17-27G. Pts received RP1/RP2 for up to 8 doses as monotherapy or in combination with nivolumab IV starting at cycle 2 or 4 for up to 2 years. Additional RP1/2 doses could be given if protocol-specified criteria were met. This analysis evaluated safety among pts receiving IT RP1/2 injections to visceral mets (defined as lung or liver mets). All safety data presented includes events occurring within 7 days after injection (except where noted). Results: As of data cutoff (RP1: 15OCT2024; RP2: 29AUG2025), there were a total of 665 RP1/2 injections into the lung (n = 125; median lung injections/pt/treatment course [c]: RP1 = 5.5 and RP2 = 8) and liver (n = 540; median liver injections/pt/c): RP1 and RP2 = 5) among 105 pts. The most common treatment-related adverse events (AEs) were pyrexia, chills, and fatigue (Table). A total of 9 pneumothorax (PTX) events occurred (within 3 days after injection) out of 125 lung injections (7.2%) in 19 pts receiving RP1/2; all cases were Grade (G) 1/2 and resolved. Only 1 pt required a chest tube for a G2 PTX event and the pt continued to receive RP1 after resolution. There were 3 bleeding events within 3 days after injection among 665 injections (0.5%) in the lung or liver in 105 pts receiving RP1/2. All bleeding events occurred in pts receiving RP2 liver injections and resolved (2/3 events resolved by the following day). Conclusions: RP1/2 injections into visceral mets were well tolerated, with a comparable safety profile to liver and lung biopsies performed in other clinical settings. The observed RPx safety profile supports the incorporation of IT injections into deep visceral tumors as part of cancer therapy. Clinical trial information: NCT03767348 ; NCT04336241 . All-grade treatment-related adverse events (>15%). RP1 RP2 Monotherapy Combination therapy Monotherapy Combination therapy n (%) Injected visc mets (n = 11) Total (n = 19) Injected visc mets (n = 46) Total (n = 151) Injected visc mets (n = 14) Total (n = 20) Injected visc mets (n = 34) Total (n = 47) Pyrexia 9 (82) 12 (63) 22 (48) 51 (34) 6 (43) 9 (45) 18 (53) 25 (53) Chills 6 (55) 6 (32) 20 (44) 43 (28) 3 (21) 5 (25) 13 (38) 19 (40) Fatigue 3 (27) 7 (37) 8 (17) 39 (26) 1 (7) 3 (15) 4 (12) 7 (15) Influenza-like illness 1 (9) 2 (11) 12 (26) 31 (21) 0 0 2 (6) 8 (17) Nausea 1 (9) 1 (5) 13 (28) 26 (17) 1 (7) 1 (5) 5 (15) 8 (17) mets, metastases; visc, visceral.

Preliminary phase 1 results of a MICA/B-targeted CAR T cell designed to overcome solid tumor escape mechanisms and avoid the requirement for conditioning chemotherapy.

2560 Background: FT836 is a multi-engineered CAR T cell targeting the conserved α3 domain of MICA/B stress ligands, enabling recognition of diverse solid tumors with additional edits including, (i) the hnCD16a FC receptor to enable multi-antigen targeting in combination with monoclonal antibodies (mAb), (ii) Sword and Shield engineering consisting of alloimmune-defense receptor (ADR) expression and CD58 deletion to coordinately avoid host recognition eliminating the need for conditioning chemotherapy (CCT), and (iii) CXCR2 and TGFβ signal redirection receptors to maximize tumor trafficking and adaptability within an immunosuppressive tumor niche, respectively. Manufactured from an iPSC-master cell bank, it is available off-the-shelf and delivered on-demand to patients (pts). Methods: The Phase 1 trial of FT836 in pts with advanced solid tumors (NCT07216105) evaluates multiple regimens including monotherapy (Regimen A), combination with EGFR-targeting mAb cetuximab or HER2-targeting mAb trastuzumab (Regimen C or E, respectively). CCT is not required and FT836 is given twice during the treatment cycle, with retreatment available for eligible patients. First dose of FT836 is administered with a 24-hour hospital stay while the 2 nd dose is given as outpatient. Results: First three pts (all MSS mCRC; median: age 45 y, prior therapies of 5, disease duration of 51 months) were treated in Regimen C dose level 1 (DL1 = 300 million cells/dose, Days 1 and 15 with cetuximab, no CCT) and completed dose limiting toxicity (DLT) evaluation (data cut-off 15 JAN 2026) with no DLTs, FT836-related serious adverse events, cytokine release syndrome (CRS), immune effector cell-associated neurotoxicity syndrome (ICANS), or graft-versus-host disease (GvHD) reported. One of the three pts demonstrated a CEA response with >50% reduction (480 ng/mL at BL; 230 ng/mL at 4 weeks after first FT836 infusion) that correlated to mass shrinkage in all target lesions in a week 7 CT scan (obtained after data cut-off date). Of the other two pts, one experienced PD while the other was not yet assessed at the time of abstract submission. FT836 was detected in peripheral blood (PB) following the first dose, with persistence observed up to 1 week. Notably, FT836 cells were detected beyond the initial PB detection in a tumor biopsy obtained at Day 22 (±3 days) indicating greater persistence in tissue compared to PB, supporting the value of additional engineered elements. EGFR and MICA/B antigens were identified in 3/3 baseline tumor biopsies, highlighting the relevance of multi-antigen targeting in driving patient outcome. Conclusions: FT836 Regimen C DL1 was well-tolerated and early clinical data supports anti-tumor activity in highly refractory mCRC where there is significant unmet need. This trial is actively enrolling and updated clinical and translational data will be presented. Clinical trial information: NCT07216105 .

Machine learning to identify biomarkers of response to immunotherapy in <i>KRAS</i> wildtype ( <i>KRASwt)</i> non-small cell lung cancer (NSCLC).

e20609 Background: KEAP1 and STK11 are associated with resistance to immune checkpoint inhibitors (ICIs) in NSCLC in KRAS -mutant disease, and are used to guide treatment selection. In contrast, biomarkers to guide treatment selection in KRAS wt NSCLC are poorly defined. We aimed to develop predictive models to guide immunotherapy selection and to identify predictive clinicogenomic biomarkers of response to immunotherapy in KRAS wt NSCLC. Methods: We analyzed patients with metastatic KRAS wt non-squamous NSCLC (nsNSCLC) treated with ICIs at multiple centers, with external validation using the US-based de-identified Flatiron Health–Foundation Medicine NSCLC Clinico-Genomic Database. XGBoost models were trained to predict progression-free survival (PFS) &gt; 6 months following first-line anti-PD-1 monotherapy (ICI-mono) or chemo-immunotherapy (ICI-chemo). Feature importance was assessed using SHAP values. The academic cohort was split 80/20 into training and test sets, and frontline-treated patients in Flatiron served as an external validation cohort. PD-L1 ≥50% (ICI-mono) and PD-L1 ≥1% (ICI-chemo) were used as baseline comparators. Results: The academic and flatiron cohorts included 1,183 and 4087 patients, respectively. The ICI-mono model demonstrated strong discrimination (test AUC = 0.71 vs PD-L1 ≥50% AUC = 0.59) and validated externally (Flatiron real-world time to next treatment [rwTTNT] HR = 0.60, p &lt; 0.001; rwOS HR = 0.60, p &lt; 0.001). The ICI-chemo model did not perform as well internally (test AUC = 0.62 vs PD-L1 ≥1% AUC = 0.53) or externally (Flatiron rwTTNT HR = 0.80, p = 0.039; rwOS HR = 0.80, p = 0.026). In both models, higher tumor mutational burden and PD-L1 were associated with improved outcomes, whereas ECOG and liver metastases were associated with worse outcomes. Genomic features were weakly predictive and did not validate in Flatiron. None of the top predictive genomic features validated in Flatiron, underscoring the importance of external validation. Given prior associations in KRAS -mutant NSCLC, KEAP1 and STK11 were evaluated in KRASwt patients: compared with double–wildtype tumors, KEAP1 -only tumors treated with ICI-mono had improved outcomes (PFS HR = 0.80, p = 0.023; Flatiron rwTTNT HR = 0.80, p = 0.031), STK11-only tumors showed no significant difference, while KEAP1 / STK11 co-mutation was associated with worse outcomes (PFS HR = 1.3, p = 0.048; Flatiron rwTTNT HR = 1.3, p = 0.013). Conclusions: In integrated modeling of KRAS wt nsNSCLC treated with ICIs, no genomic alterations were consistently predictive of response. However, univariate analyses suggest that KEAP1 and STK11 mutations exert distinct and non-additive effects in KRAS wt disease, contrasting with their role in KRAS -mutant NSCLC. These findings have potential implications for treatment intensification strategies, including selective use of anti-CTLA-4 therapy in KRAS wt NSCLC.