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Selective internal radiation therapy with yttrium-90 resin microspheres followed by lenvatinib plus PD-1 inhibitor for large or huge advanced-stage hepatocellular carcinoma: A retrospective cohort study from China.

581 Background: Yttrium-90 resin microspheres have been introduced into China in recent years, but the efficacy or safety on Chinese patients are rarely reported. This study aimed to evaluate the efficacy and safety of selective internal radiation therapy (SIRT) with yttrium-90 resin microspheres followed by lenvatinib and PD-1 inhibitor in Chinese patients with large (5.1–10.0 cm in diameter) or huge (>10.0 cm) advanced-stage hepatocellular carcinoma (HCC). Methods: Data of large or huge Barcelona Clinic Liver Cancer stage C HCC patients treated with SIRT followed by lenvatinib plus PD-1 inhibitor from November 2022 to October 2023 were prospectively collected and retrospectively analyzed. Key endpoints included overall survival (OS), progression-free survival (PFS), complete response rate (CRR), objective response rate (ORR), disease control rate (DCR) based on modified Response Evaluation Criteria in Solid Tumors, and adverse events (AEs) graded based on Common Terminology Criteria for Adverse Events v5.0. Risk factors affecting PFS were analyzed using univariate and multivariate Cox regression models. Results: A total of 30 patients (27 males, 3 females; mean age 54 ± 11 years) were included. The mean longest diameter of the tumor was 9.6 ± 4.2 cm (range: 5.2–17.6 cm). Nineteen (63.3%) patients had more than three intrahepatic lesions, 15 (50.0%) had vascular invasion, and 13 (43.3%) had extrahepatic metastasis. Sixteen (53.3%) patients had undergone prior anticancer therapies. Two patients received two SIRT procedures, and the rest had one. Lenvatinib and PD-1 inhibitor treatment was initiated 3–7 days after the initial SIRT procedure. CRR was 20.0%, ORR was 73.3%, and DCR was 90.0%. Median PFS was 8.0 months (95% CI, 5.6–10.4), and median OS was not reached. OS rates at 6, 12, and 18 months were 93%, 74%, and 74%, respectively. Univariate and multivariate analysis indicated that baseline alpha-fetoprotein levels, baseline eosinophil count, and neutrophil-to-lymphocyte ratio at 1 month after SIRT were independent risk factors for PFS. AEs of any grade occurred in 86.7% of patients, with grade 3 AEs in 23.3%, and no grade 4/5 AEs were recorded. Conclusions: SIRT followed by lenvatinib and PD-1 inhibitor demonstrates promising efficacy and a favorable safety profile in Chinese patients with large or huge advanced-stage HCC.

Cohort-level patient-derived organoid assays and prediction of clinical trial outcomes in PDAC.

785 Background: Clinical trials are one of the major barriers in contemporary drug development. Improving the number of therapeutic solutions for patients whilst limiting the financial burden of healthcare systems will require dramatically improving clinical trial success rates. Functional assays based on patient-derived organoids (PDO) are a promising new tool for derisking clinical development of new therapies, but their use has been limited due to small cohort sizes and the absence of systematic validation studies. Methods: We have assembled a collection of 70 demographically relevant PDAC PDOs. Each PDO was screened with a 22-drug panel including standard of care, chemotherapies and targeted therapies. Using a best-in-class patient response prediction model we generate cohort scale estimations of overall response rates (ORR) and progression-free survival (PFS). The estimations are compared with data from published clinical trials to determine the validity of the approach. Results: The PDOs exhibit representative treatment histories in terms of number of lines of treatment (mean = 1.60) and treatment types (prior treatment types: folfirinox = 68.6%, gemcitabine = 50%). All the organoids’ mutational profile, past patient treatments and subsequent responses to future lines were analyzed and compared to the distributions observed in the clinic. The cohort-level drug efficacy on our PDO collection matches retrospective clinical trial ORRs reported in the literature. Furthermore, our preclinical assay predicts the relative performance of drugs in different clinical trial arms. Conclusions: We report that large-scale PDO-based assays predict clinical ORR and PFS with best-in-class accuracy. This work shows that well-characterized PDO collections can be used to improve the success rates of clinical studies for new potential treatments in PDAC.

Enhancing Photovoltaically Preferred Orientation in Wide‐Bandgap Perovskite for Efficient All‐Perovskite Tandem Solar Cells

Abstract Wide‐bandgap perovskite solar cells (WBG PSCs) have promising applications in tandem devices yet suffer from low open‐circuit voltages ( V OC s) and less stability. To address these issues, the study introduces multifunctional nicotinamide derivatives into WBG PSCs, leveraging the regulation on photovoltaically preferential orientation and optoelectronic properties via diverse functional groups, e.g., carbonyl, amino. Isonicotinamide (IA) molecule emerges as the most effective agent, enhancing crystallization kinetics and defect passivation due to its unique planar spatial configuration. Incorporating IA into WBG perovskites improves the (100) preferred crystal orientation, reduces trap density, and enables well‐matched energy band alignment. High‐performance 1.77 eV WBG PSCs are achieved with a champion power conversion efficiency of 19.34% and a V OC of 1.342 V, leading to the fabrication of the best‐performing all‐perovskite tandem solar cell with a PCE of 28.53% (certified 28.27%) and excellent operational stability, maintaining over 90% of the initial efficiency under 1 sun illumination for 600 h.

What is the optimal treatment strategy of salvage line treatment after progression on anti-epidermal growth factor receptor monoclonal antibody in patients with tissue <i>RAS/BRAF</i> wild-type metastatic colorectal cancer?

138 Background: Trifluridine/tipiracil (FTD/TPI) plus bevacizumab (BEV) and anti-epidermal growth factor receptor (EGFR) monoclonal antibody (mAb) re-challenge are treatment options for tissue RAS/BRAF wild-type (WT) metastatic colorectal cancer (mCRC) in salvage line, although the optimal treatment sequence of salvage line remains unclear. Methods: RAS/BRAF WT mCRC patients refractory to anti-EGFR mAb were retrospectively enrolled at a single cancer institute from November 2017 to April 2024. We compared responses, progression-free survival (PFS), and overall survival (OS) between Group A (anti-EGFR mAb re-challenge given first) and B (FTD/TPI plus BEV given first). We compared responses between Group C (treated with anti-EGFR mAb re-challenge at any line) and D (treated with FTD/TPI plus BEV at any line). We explored the clinical factors related to the treatment efficacy using multivariate analysis. Results: A total of 89 patients (median age, 63 years) were included. The cohort included 74 patients with a primary lesion in the left-sided colon, while 15 patients had a primary lesion in the right-sided colon. The response rate (RR) was 3.4%. The disease control rate (DCR) was 52.8%. The median PFS (mPFS) and OS (mOS) were 3.5 months (95% confidence interval [CI], 2.8-4.2) and 12.8 months (95% CI, 8.8-15.7) respectively. Two of 18 patients (11.1%) in Group A and 1 of 71 patients (1.4%) in Group B achieved partial response (PR). The RR of Group C was significantly higher than Group D (9.6% vs 1.2%; p = 0.031). Both PFS and OS showed no significant difference between Group A and B (mPFS: 3.3 vs 3.9 months; hazard ratio [HR], 1.08; 95% CI, 0.63-1.84; p = 0.79) (mOS: 12.8 vs 15.0 months; HR, 0.90; 95% CI, 0.49-1.65; p = 0.72). Multivariate analysis identified that primary tumor resection was associated with PFS (HR, 0.44; 95% CI, 0.25–0.80; p = 0.0068) and primary tumor resection (HR, 0.34; 95% CI, 0.18–0.65; p = 0.0010) and serum CA19-9 level (HR, 1.75; 95% CI, 1.02-3.00; p = 0.043) were associated with OS. Conclusions: No significant survival difference was observed between patients administered anti-EGFR mAb re-challenge first and those administered FTD/TPI plus BEV first, whereas the RR of anti-EGFR mAb re-challenge is significantly higher than that of FTD/TPI plus BEV.

Q-TWiST analysis of pembrolizumab or placebo plus chemotherapy for patients with advanced HER2-negative gastric or gastroesophageal junction (G/GEJ) cancer in KEYNOTE-859.

376 Background: In the phase 3 KEYNOTE-859 study (NCT03675737; N = 1579), patients (pts) with locally advanced or metastatic HER2-negative G/GEJ cancer treated with first-line pembrolizumab (pembro) plus chemotherapy (chemo) had a significant and clinically meaningful improvement in OS with manageable toxicity vs placebo (pbo) plus chemo while maintaining HRQoL in the intention-to-treat and prespecified PD-L1 combined positive score (CPS) populations. We report data from an analysis of quality-adjusted time without symptoms of disease progression or toxicity (Q-TWiST). Methods: Q-TWiST is a measure of survival weighted by health states utility values. The analysis categorized survival time into 3 health states: time with grade ≥3 AEs (toxicity [TOX]) and time without symptoms or toxicities (TWiST)—both before disease progression or death—and relapse (REL), defined as time from disease progression to death. Q-TWiST was calculated as the restricted mean survival time (RMST) spent in each state, with a weighted health state utility for that state. Average utility weights were derived based on pooled EQ-5D-5L scores using the US mapping algorithm and standardized base case utility weights. Relative gains in Q-TWiST of ≥10% and ≥15% were “clinically important” and “clearly clinically important,” respectively, as reported in the literature. Treatment difference 95% CIs were generated using the nonparametric bootstrapping method. Data are reported for all randomly assigned pts and pts with PD-L1 CPS ≥1 and CPS ≥10 tumors. The data cutoff date was August 22, 2023. Results: At the maximum follow-up of 56 mo for pembro plus chemo vs pbo plus chemo, RMST was 5.16 vs 2.86 mo for TOX, 7.77 vs 5.87 mo for TWiST, and 6.85 vs 7.12 mo for REL. Between-treatment differences are shown in the table. The difference in restricted mean Q-TWiST and relative gain favored pembro plus chemo. Conclusions: A clearly clinically important Q-TWiST gain was observed for pembro plus chemo vs pbo plus chemo in all pts with advanced HER2-negative G/GEJ cancer and pts with PD-L1 CPS ≥1 and CPS ≥10 tumors. Clinical trial information: NCT03675737 . All ptsN = 1579 PD-L1 CPS ≥1n = 1235 PD-L1 CPS ≥10n = 553 RMST in TOX, mo (95% CI) 2.30(1.28 to 3.44) 2.65(1.46 to 3.99) 4.28(2.08 to 6.41) RMST in TWiST, mo (95% CI) 1.90(−0.02 to 3.79) 2.28(0.07 to 4.49) 3.72(0.43 to 7.19) RMST in REL, mo (95% CI) −0.28(−2.43 to 2.01) −0.22(−2.88 to 2.39) −0.45(−4.52 to 3.71) Restricted meanQ-TWiST, mo (95% CI) a 3.31(2.10 to 4.59) 3.98(2.60 to 5.43) 6.45(4.26 to 8.74) Relative Q-TWiST gain, % (95% CI) a 20.90(12.49 to 30.56) 25.34(16.04 to 36.26) 38.05(23.21 to 56.59) Restricted meanQ-TWiST, mo (95% CI) b 2.91(1.58 to 4.14) 3.50(2.02 to 4.88) 5.63(3.31 to 7.99) Relative Q-TWiST gain, % (95% CI) b 18.38(9.78 to 27.46) 22.27(12.65 to 32.52) 33.19(18.76 to 49.97) a Based on US mapping algorithm. b Based on standardized base case utility weights.

Real world data and biomarker analysis of the efficacy and safety of PD-1 inhibitor combined with chemotherapy in first-line treatment of advanced gastric cancer.

342 Background: With the publication of several clinical research results, the efficacy of ICI combined with chemotherapy has gradually been recognized in HER-2 negative advanced GC field. We analyzed the efficacy of 1st-line PD-1 inhibitor combined with chemotherapy in advanced GC patients using real-world data and conducted exploratory analysis. We aim to identify factors that can predict treatment efficacy, and provide a basis for clinical practice. Methods: We prospectively collected data from GC patients between November 2020 and April 2024. The clinical staging was stage IV. All patients were HER2 negative and pMMR. All patients received SOX regimen chemotherapy combined with PD-1 inhibitor. Blood samples were collected for exploratory analysis. Results: A total of 190 GC patients with histological diagnosis of adenocarcinoma were included from November 1, 2020 to April 1, 2024. As of June 1, 2024, the median follow-up time was 11.75 (95% CI 10.65-13.00) months. Among them, 174 had measurable lesions. 94 patients achieved PR, and 55 patients achieved SD. The ORR and DCR were 61.9% (95% CI 48.8-73.4%) and 96.8% (95% CI 89.0-99.6%), respectively. The survival analysis results indicated that the mPFS and mOS were 9 (95% CI 7.9-14.2) and 27 (95% CI 20- not reached) months. We conducted risk factor analysis on patients , age, gender, CPS, HER2 expression, EGFR expression and EBER status. Age, gender, CPS, EBER status and EGFR expression are not risk factors affecting survival. Specifically, the expression level of HER2 was significantly correlated with therapeutic efficacy. The results indicated that the HER2 expression level was significantly correlated with ORR. In terms of survival analysis, the PFS of treated patients with HER2 ‘2+’ was significantly longer than that of treated patients with HER2 ‘1+’, and there was a trend of prolonged OS, but the statistical difference was not reached. We collected baseline blood samples from 62 patients and performed ctDNA testing. In terms of PFS, the patients with SNV in SMARCA4 and RASA1 was significantly shorter than that of wild-type patients with SMARCA4 ( p = 0.02) and RASA1 ( p = 0.043). The patients with CNV in EXT1 was significantly shorter than those with wild-type in EXT1 ( p = 0.00046). In terms of OS, patients with SNV in BRCA2, TP53, and STK11 had significantly shorter OS than those with wild-type BRCA2 ( p = 0.033), TP53 ( p = 0.048), and STK11 ( p = 0.0083). The patients with CNV in MYC and EXT1 had shorter OS than those with wild-type MYC ( p &lt; 0.0001) and EXT1 ( p &lt; 0.0001) patients. Conclusions: Real-world data showed that 1st-line treatment with PD-1 inhibitor combined with SOX had shown good efficacy in advanced GC patients. The HER2 expression level in HER2 negative GC may become a direction for further exploration. The EXT1 mutation can serve as a potential predictor, and further investigation is warranted. Clinical trial information: NCT06034964 .

Leech‐Inspired Amphibious Soft Robot Driven by High‐Voltage Triboelectricity

AbstractLeech locomotion, characterized by alternating sucker attachment and body contraction provides high adaptability and stability on complex terrains. Herein, a leech‐inspired triboelectric soft robot is proposed for the first time, capable of amphibious movement, climbing, and load‐carrying crawling. A high‐performance triboelectric bionic robot system is developed to drive and control electro‐responsive soft robots. Its core components include: i) a leech‐inspired soft robot (LSR) made from segmented dielectric elastomer muscles. ii) The triboelectric sucker produces anisotropic frictional forces. iii) The multi‐channel high‐voltage output triboelectric nanogenerator (HDC‐TENG) effectively drives the LSR. iv) The high‐voltage triboelectric control unit adapted for the HDC‐TENG enables flexible LSR control. Using the scalable structure of the dielectric elastomer muscles enables the LSR to achieve a maximum crawling speed of 0.39 body lengths per minute on land (45 mm min−1) and 0.22 body lengths per minute in liquid (30.5 mm min−1). It can also carry a payload of 11.55 grams on acrylic while crawling. This research provides a sustainable and promising new solution for self‐powered high‐voltage energy sources suitable for electro‐responsive soft robots.

Cost-effectiveness of NALIRIFOX compared to other first-line treatments for metastatic pancreatic cancer.

733 Background: NALIRIFOX was recently approved for first-line treatment of metastatic pancreatic cancer, where combination chemotherapy remains the main treatment modality. We conducted a cost-effectiveness analysis of NALIRIFOX compared to both FOLFIRINOX and gemcitabine/protein-bound paclitaxel (GP). Methods: A partitioned survival model with three health states (progression-free, post-progression and death) was constructed to model the disease course. Using published data from NAPOLI-3, parametric survival curves were generated for NALIRIFOX, from which survival curves for FOLFIRINOX and GP were extrapolated using pooled efficacy data reported by a network meta-analysis of clinical trials. Model inputs were retrieved from the literature or other publicly available resources. Specifically, drug acquisition costs were from average wholesale prices in the Red Book while administration, disease monitoring and supportive care costs were from the CMS Physician Fee Schedule. Utility values to estimate quality-adjusted life years (QALY) were from the CALGB80303 trial. Adverse effects that were considered included anemia, neutropenia, febrile neutropenia, thrombocytopenia, diarrhea, peripheral neuropathy, nausea and vomiting, and fatigue. Adverse effect rates were based on data pooled from clinical trials while costs and disutility were obtained from a secondary analysis of claims data and a clinician survey, respectively. The time horizon was 5 years and utilized a third-party payer perspective. Both costs ($USD 2024) and outcomes were discounted at 3% annually. A probabilistic sensitivity analysis was conducted by varying model parameters based on 95% confidence intervals if known or 10% in both directions otherwise. Results: The overall cost associated with NALIRIFOX was $129,314, followed by GP ($104,593) and FOLFIRINOX ($41,528). Among the 3 regimens, NALIRIFOX incurred the highest treatment-related cost ($105,533) but the lowest adverse effects management cost ($16,541). On average, patients on NALIRIFOX gained a total of 1.14 life years (LY) or after adjusting for utility, 0.86 QALY. FOLFIRINOX led to 1.09 LY or 0.82 QALY while GP resulted in 0.99 LY or 0.75 QALY. Due to its higher cost and lower survival benefit, GP was dominated by FOLFIRINOX. Compared to FOLFIRINOX, the incremental cost-effectiveness ratio (ICER) of NALIRIFOX was $1,952,062/QALY. In our sensitivity analysis, the probability of NALIRIFOX being cost-effective was 0% at all conventional ICER thresholds up to $200,000/QALY. Conclusions: Due to the high drug acquisition cost, the ICER of NALIRIFOX far exceeds currently acceptable thresholds for economic value and NALIRIFOX is considered not cost-effective. This is despite that in our model among first line treatments for metastatic pancreatic cancer, NALIRIFOX was associated with reduced costs for managing adverse effects.

TROP2 expression in small bowel adenocarcinoma: A potential target for novel therapeutic strategies.

799 Background: Small bowel adenocarcinoma (SBA) is a rare cancer with limited chemotherapy options. To explore TROP2 as a potential therapeutic target for SBA and develop new treatment strategies, we examined TROP2 protein expression in SBA and analyzed associated clinicopathological features and prognosis, including PD-L1 expression levels in the same tumor samples from our previous studies. Methods: We retrospectively reviewed patients diagnosed with SBA who underwent adjuvant or palliative chemotherapy between July 2010 and July 2023 at our hospital. Immunohistochemistry staining of TROP2 (clone: SP295) was performed for pathological samples. The intensity of TROP2 membranous staining in tumor cells was classified as 0 (absent), 1 (weak to moderate), or 2 (strong). TROP2 positivity was defined as intensity 1 with ≥ 50% expression or intensity 2 with ≥ 10% expression. We also assessed overall survival (OS) in patients receiving palliative chemotherapy to examine the association between prognosis and TROP2, excluding microsatellite instability-high (MSI-H) patients treated with immunotherapy. Results: Pathological samples and clinical data were available for 51 patients. The median age was 63 years (range: 23–82), and 76% were male. Most patients (94%) had a performance status (PS) of 0–1. The primary lesion was in the duodenum in 49% of patients and in the jejunum or ileum in 51%. Surgery and adjuvant chemotherapy resulted in no recurrence in 12% of patients, while 88% received oxaliplatin-based palliative chemotherapy for unresectable SBA. Among those with unresectable SBA, 8% (4/51) had MSI-H and were treated with immunotherapy. TROP2 positivity was 84.3% (43/51). There were no differences in age, sex, or primary lesion between the TROP2-positive and TROP2-negative groups. In this cohort, the median CPS was 3 (range, 0–60). CPS was lower in TROP2-positive samples compared to negative samples (median CPS 7.9% vs. 23.4%, p = 0.030). However, all MSI-H cases were found to be TROP2-positive. Among patients receiving palliative chemotherapy, excluding those with MSI-H treated with immunotherapy, OS did not differ significantly between TROP2-positive and TROP2-negative patients (17.0 months vs. 9.2 months, HR 0.70, p = 0.480). Even after adjusting for age and PS, TROP2 expression was not identified as a prognostic factor. Conclusions: Our study highlighted that TROP2 is frequently expressed in SBA, suggesting it could be an effective therapeutic target for new treatment strategies. Further investigation is needed to confirm its potential.

Zanidatamab dose optimization in patients with HER2-positive biliary tract cancer (BTC).

546 Background: Zanidatamab (zani) is a dual HER2-targeted bispecific antibody that binds 2 distinct HER2 domains, resulting in receptor crosslinking, clustering, and internalization as well as leading to reductions in cell-surface levels of HER2, phosphorylation of HER family members (EGFR, HER2, and HER3), downstream signaling, and ligand-dependent and -independent proliferation. Zani also induces complement-dependent cytotoxicity as well as antibody-dependent cellular cytotoxicity and phagocytosis. In the phase 2 HERIZON-BTC-01 study (Study 203), zani 20 mg/kg Q2W demonstrated a 41.3% confirmed objective response rate (cORR) and a manageable safety profile in patients (pts) with previously treated HER2+ BTC (IHC3+/2+ and ISH+). The objective of this analysis is to report optimal dose selection for zanidatamab in patients with HER2+ BTC through pharmacokinetic modeling. Methods: Source data included the phase 1 ZW25-101 study (Study 101; NCT02892123), Study 203 (NCT04466891), and in vitro study for ligand-dependent growth inhibition (LDGI) in HER2-expressing human cancer cell lines. In the LDGI study, cancer cells were cultured in media containing epidermal growth factor and were treated with different zani concentrations. The IC90 value for LDGI was obtained by nonlinear regression using the logistic dose-response model. To assess target saturation, the population pharmacokinetic model was used to simulate clearance at steady state following 5-30 mg/kg Q2W. The clinical utility of zani was evaluated based on the correlation of zani concentrations with both efficacy and safety. Results: Study 101 included 192 patients with HER2-expressing solid tumors (dose ranged from 5-30 mg/kg including QW, Q2W, and Q3W). The Ctrough values following the first zani 5 mg/kg QW dose were below the IC90 (25.0 μg/mL) for LDGI, and no confirmed responses were observed at this dose. The Ctrough values following the first zani dose of 10 mg/kg QW or 20 mg/kg Q2W were above IC90 and the 2 dose levels demonstrated a cORR of 25% and 28.6%, respectively. The simulated clearance suggests that the target-mediated elimination pathway was saturated at the dose level of 20 mg/kg Q2W, since clearance was comparable to that of the higher dose of 30 mg/kg Q2W. The efficacy and safety of 20 mg/kg Q2W was further evaluated in 87 pts with HER2-amplified BTC enrolled in Study 203. The clinical utility analysis based on the data from Study 203 demonstrated that the majority of pts had an exposure range on the plateau part of the efficacy curve. Conclusions: The zani dose of 20 mg/kg Q2W is expected to maximize the clinical benefit for pts with HER2+ BTC based on: reaching the desired target exposure (IC90 for LDGI), saturating target-mediated elimination pathway, and the clinical utility analysis of safety and efficacy. Higher exposures are not expected to result in higher responses. Clinical trial information: NCT02892123 , NCT04466891 .

A phase 1 dose escalation/expansion study of GSK5764227 (GSK’227), a B7-homolog 3 (B7-H3) protein targeted antibody-drug conjugate (ADC), in patients with advanced solid tumors, including gastrointestinal (GI) cancers.

TPS847 Background: B7-H3 is an immune checkpoint protein overexpressed in multiple solid tumors with limited expression in normal tissues. GSK’227 (HS-20093), a novel B7-H3-targeted ADC, is composed of a human anti–B7-H3 monoclonal antibody linked to a topoisomerase I inhibitor via a protease-cleavable linker, and has shown acceptable safety and promising antitumor activity in patients of Asian origin with advanced solid tumors (NCT05276609; NCT05830123). The current study will evaluate the safety, tolerability, efficacy, and pharmacokinetics (PK) of GSK’227 in patients with solid tumors, including GI cancers, in a global population. Methods: This two-part (dose-escalation [1a] and expansion [1b]) global, open-label, Phase I study (NCT06551142) will enroll ~260 patients, with enrollment currently ongoing. Key eligibility includes: aged ≥18 years, histologically confirmed advanced solid tumors, including those with colorectal cancer, esophageal squamous cell carcinoma, and pancreatic cancer, with measurable disease per Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1), Eastern Cooperative Oncology Group (ECOG) performance status of 0–1, and no prior B7-H3 treatment. Eligible patients will receive intravenous GSK’227 every 3 weeks (Q3W) until progression, toxicity, loss to follow-up, or death. For Phase 1a, a Bayesian optimal interval design will be used to determine the maximum tolerated dose. Phase 1a primary endpoints are safety and tolerability, including incidences of adverse events (AEs) and serious AEs. Secondary endpoints include objective response rate (ORR), disease control rate, duration of response, immunogenicity, and PK. The Phase 1b primary endpoint is progression-free survival (extensive-stage small cell lung cancer cohort) or ORR (GI and other solid tumors cohort). Secondary endpoints include additional efficacy assessments, PK, safety and tolerability. For Phase 1a and 1b, efficacy will be assessed per RECIST v1.1, with imaging conducted Q6W from first dose then Q12W after 24 weeks. Safety follow-up will be conducted at 30, 60, and 90 (±7) days after the last dose. Safety, tolerability, and efficacy analyses will be conducted using descriptive statistics and, for efficacy analyses, point estimates with 2-sided 95% confidence intervals. This abstract was previously submitted to the European Society for Medical Oncology (ESMO) Immuno-Oncology Congress 2024 and is submitted on behalf of the original authors with their permission. Funding: GSK (Study 223054). Medical writing support was provided by Avalere Health, funded by GSK. Clinical trial information: NCT05830123 .

Comparative outcomes of neuroendocrine tumors in the historically underserved population of Bronx, NY: Montefiore Einstein Comprehensive Cancer Center.

671 Background: Neuroendocrine tumors (NETs) pose different clinical implications based upon age at diagnosis, with regards to early-onset (EO&lt;50yrs) versus late-onset (LO&gt;=50yrs) disease. While primary-tumor resection is crucial for localized NETs, its benefit in metastatic cases without metastasectomy remains uncertain. This study examines variables associated with survival in EO versus LO cases, including primary tumor resection. Methods: A retrospective cohort of 91 patients with gastrointestinal(GI)-NETs were identified as part of an IRB-approved project. Disease-stage (local vs. metastatic), tumor grade (G1-3), 5-year-survival, primary-tumor removal, and race/ethnicity were included in this analysis. Results: Among all patients, 31.9% identified as Hispanic, 33% as non-Hispanic Black, 22% as non-Hispanic White, and 13.1% as other. Among all patients, 79 were classified as G1/G2. Among LO patients, 87.5% (n=63) were G1/G2, among which 46% (n=29) were metastatic. Among EO patients, 84% (n=16) were G1/G2, among which 68.8% (n=11) were metastatic. In the LO group with G1/G2 tumors, 5-year survival rate was 48.3% for metastatic disease and 58.8% for localized disease. For EO with G1/G2 tumors, the 5-year survival rate was 72.7% for metastatic disease and 80% for localized disease. In the EO G1/G2 group, 5 of the 11 patients with metastatic disease had primary tumor removal without metastasectomy with 100% 5-year survival rate. In the LO G1/G2 group, 7 of 29 metastatic patients had primary tumor removal without metastasectomy, with 86% 5-year survival rate. Resection of primary tumor (without metastasectomy) in patients with metastatic G1/G2 NETs was associated with improved 5-year survival, independent of age at diagnosis ( p-value =0.008), as shown in the table. Conclusions: This study helps to emphasize the importance of primary tumor removal in improving survival outcomes for patients with metastatic low-grade GI-NETs, regardless of age. Further investigation is warranted to study the role of certain imperative variables such as site of metastases, number of metastases, and patient co-morbidities. Survival outcomes based on primary tumor removal in metastatic low-grade GI-NETs. No 5-year survival 5-year survival Primary tumor removal without metastasectomy 1 11 No surgery 12 8

Pembrolizumab plus chemotherapy versus placebo plus chemotherapy in patients with advanced HER2-negative gastric or gastroesophageal junction (G/GEJ) adenocarcinoma enrolled in the Republic of Korea: KEYNOTE-859.

428 Background: After a median follow-up of 41.6 mo, data from the global phase 3 KEYNOTE-859 study (NCT03675737; N = 1579) continued to show that use of pembrolizumab (pembro) plus chemotherapy (chemo) provided a significant and clinically meaningful improvement in overall survival (OS), with manageable safety, versus placebo (pbo) plus chemo for patients (pts) with locally advanced or metastatic HER2-negative G/GEJ adenocarcinoma. This post hoc analysis evaluated the safety and efficacy of pembro plus chemo in pts enrolled in KEYNOTE-859 in the Republic of Korea. Methods: Eligible pts aged ≥18 years with locally advanced unresectable or metastatic HER2-negative G/GEJ adenocarcinoma, measurable disease per RECIST v1.1, and an ECOG performance status (PS) of 0 or 1 were randomly assigned 1:1 to receive pembro 200 mg or pbo IV Q3W for ≤35 cycles. All pts received investigator’s choice of chemo (FP or CAPOX). The primary end point was OS. Secondary end points included progression-free survival (PFS), objective response rate (ORR), and duration of response (DOR) per RECIST v1.1 by blinded independent central review, and safety. Efficacy end points were evaluated in all randomly assigned pts (intention to treat). Results: A total of 150 pts (66, pembro plus chemo; 84, pbo plus chemo) from the Republic of Korea were enrolled. The median time from randomization to database cutoff (August 22, 2023) was 48.1 mo (range, 32.7-56.8). Baseline characteristics were generally well balanced between treatment groups. Most pts were male (71.3%) with an ECOG PS of 1 (66.7%); 43.3% of pts had ≥3 metastases. The median OS was 19.5 mo (95% CI, 14.2-26.2) for pembro plus chemo versus 15.2 mo (95% CI, 11.7-19.8) for pbo plus chemo (HR, 0.80; 95% CI, 0.55-1.15). Additional efficacy data are reported in the Table. Treatment-related adverse events occurred in 63 pts (95.5%) in the pembro plus chemo group and 78 pts (92.9%) in the pbo plus chemo group; 39 (59.1%) and 31 (36.9%) pts, respectively, were grade 3 or 4. No treatment-related deaths occurred. Conclusions: Consistent with the global results, clinical outcomes favored pembro plus chemo versus pbo plus chemo with manageable safety in pts from the Republic of Korea with HER2-negative G/GEJ adenocarcinoma enrolled in KEYNOTE-859. Clinical trial information: NCT03675737 . Pembro + chemon = 66 Pbo + chemon = 84 Median PFS (95% CI), mo a 11.0 (6.9-17.6) 7.2 (5.6-8.9) PFS HR (95% CI) b 0.74 (0.48-1.13) ORR, % (95% CI) c 53.0 (40.3-65.4) 46.4 (35.5-57.6) Median DOR (range), mo 15.0 (1.4+ to 50.8+) 6.9 (1.4+ to 44.3+) Responses lasting ≥24 mo, a % 42.6 23.6 a Based on Kaplan-Meier estimates. b Based on the unstratified Cox regression model with the Efron method of tie handling with treatment as a covariate. c Based on the stratified Miettinen and Nurminen method with strata weighting by sample size.

Local Chemical Enhancement and Gating of Organic Coordinated Ionic‐Electronic Transport (Adv. Mater. 5/2025)

A systematic review and meta-analysis on evaluating the efficacy and safety of netupitant/palonosetron compared to aprepitant for the prevention of chemotherapy-induced nausea and vomiting in patients undergoing emetogenic chemotherapy.

823 Background: NEPA stands as the exclusive oral fixed combination antiemetic agent, comprising the highly selective NK1 receptor antagonist (RA) netupitant (300 mg) and the clinically distinct 5-HT3 RA, palonosetron (0.5 mg). Administered in a single dose, NEPA concurrently modulates two critical antiemetic pathways, offering a more convenient and straightforward alternative for sustained protection against chemotherapy-induced nausea andvomiting (CINV). Numerous studies have assessed NEPA's efficacy relative to other Neurokinin (NK) 1 receptor antagonists (RAs), notably aprepitant (APR), widely utilized for CINV. Our study critically examines the efficacy and safety of NEPA versus APR for preventing CINV in patients receiving emetogenic chemotherapy, drawing insights from recent studies. Methods: Studies comparing NEPA versus APR for the prevention of CINV in patients receiving emetogenic chemotherapy until August 2024 were systematically searched on Medline, Embase, and Cochrane Library. Notably, no systematic review or meta-analysis of pooled data from existing studies is currently present in the literature. Results: Following screening, four studies were deemed eligible for inclusion in the meta-analysis, encompassing a total of 2079 patients. The NEPA group comprised 1047 individuals, while the APR group comprised 1032 subjects. The primary outcome included the comparison of subjects experiencing no nausea in overall phases. Secondary outcomes involved subjects with no emesis and no nausea in the acute and delayed phases. A significant reduction in the risk of overall nausea in the NEPA group was observed compared to the APR group after Moderately Emetogenic Therapy (MEC) or Highly Emetogenic Therapy (HEC) [Risk Ratio (RR) of 1.07, 95% Confidence Interval (CI) = 1.01-1.13, P = 0.01). A trend of reduced emesis during both acute [RR = 1.08, 95% CI = 0.95-1.22, P = 0.24] and delayed periods [RR = 1.03, 95% CI = 0.99-1.07, P = 0.15] was observed in the NEPA group, but the results were not statistically significant. Significant nausea in the acute and delayed post-chemotherapy periods exhibited a similar trend (RR = 1.02, 95% CI = 0.98-1.06, P = 0.43) and (RR = 1.04, 95% CI = 0.98-1.10, P = 0.23) respectively, with non-significant statistical outcomes. Conclusions: Our analysis suggests that the use of NEPA results in better control of nausea in overall phases compared to Aprepitant for the prevention of CINV in patients receiving emetogenic chemotherapy. However, NEPA demonstrates comparable efficacy to aprepitant in achieving control of nausea and emesis when the symptoms are stratified in acute and delayed phases. Nevertheless, further studies are warranted for a comprehensive comparison between NEPA and Aprepitant for the prevention of CINV.

Regional variation in trajectories of colon cancer mortality, 2012-2021.

41 Background: Colorectal cancer (CRC) is the fourth most common cancer by incidence in the United States in 2024, and the second most common cause of cancer mortality in Texas. Rates of advanced CRC at diagnosis and cancer related mortality are higher in rural areas. Here we explore the variation in mortality trends across the eleven public health regions (PHR) of Texas from 2012 to 2021. Methods: We conducted a population-based cohort study of colon cancer mortality in Texas over the period 2012 through 2021. We queried the National Cancer Institute Surveillance, Epidemiology and End Results Program (SEER) for county level colon cancer deaths in Texas over the most recent available decade. Counties were aggregated into the eleven public health regions defined by the Texas Department of State Health Services. We calculated age-adjusted mortality rates (AAMRs) per 100,000 population using the direct standardization method based on the age group weights from the 2000 standard US population. Confidence intervals for AAMR were derived by estimating the standard error as the AAMR divided by square root of number of mortalities. The annual percent changes (APC) in AAMR were tested using negative binomial regression. Subgroup analyses included age group, sex, and race/ethnicity. Results: A total of 33,591 colon cancer mortalities were included in the study. Total colon cancer mortalities rose from 2,973 in 2012 to 3,800 in 2021. The statewide AAMR was initially 12.4 (95% CI 12.0 to 12.9), and did not change over the study period (APC -0.1% [95% CI -0.5% to 0.2%]; p = 0.5155) ending at (AAMR 12.5 [95% CI 12.1 to 12.9]). Divergent trajectories for AAMR across public health regions were observed. The largest decline in AAMR (APC -3.9% [95% CI -6.3 to -1.6]; p = 0.0013) occurred in region 10, where the AAMR fell from 14.2% [95% CI 8.6 to 19.7]) to AAMR 11.0 [95% CI 6.8 to 15.1]. Region 6 also saw a significant decrease (APC -1.1% [95% CI -1.8% to -0.4%]; p = 0.0029) falling from AAMR 12.2 [95% CI 11.3 to 13.2] to AAMR 11.2 [95% CI 10.4 to 11.9]. The largest significant increasing trend (APC +2.3% [95% CI 0.6% to 4.1%]; p = 0.0089) for AAMR was observed for region 9 rising from AAMR 12.4 (95% CI 9.6 to 15.3) to AAMR 15.4 (95% CI 12.3 to 18.4). Conclusions: Our analysis showed a significant and increasing trend in CRC related mortality in PHR 9. This region, colloquially termed West Texas, consists of 30 counties of which over 86% are designated as rural. Rural areas struggle with higher poverty, lower degree of higher education attainment, less access to healthcare and physicians, and a higher frequency of uninsured status. West Texas in particular also has a higher rate of smoking and obesity. However, PHR 10, which shares many similarities with PHR 9 such as rurality (83.3%) and similar socioeconomic and geographic challenges, witnessed the greatest decline in AAMR of the eleven PHR's in the same time frame, suggesting the presence of other factors which may be contributing to this increase.

Communication of cancer biomarker testing results: What patients need.

51 Background: As colorectal cancer (CRC) biomarker testing becomes more widespread and important for treatment decisions, understanding testing results can improve patient engagement, shared decision-making, and facilitate clinical trial enrollment. Our experience in the online 12,000+ member CRC community COLONTOWN (CT), suggests that communication of biomarker results to patients is not ideal. To learn more, we surveyed CT members on their biomarker testing experience. Methods: An online survey posted in CT in September 2024 had questions on testing received (what was tested and how), test results experience (communication before testing and after results, patient understanding and resulting impact), suggested provider statements on biomarker results (statements patients prefer) and disease and respondent details. Results: Of 83 respondents, 70% had testing that included at least 3 common CRC biomarkers; the following are results from this group. Until receipt of results, 30% were unaware that biomarker testing was being done, and 56% first reviewed results without a clinician. Only 17% of respondents felt that nothing was lacking in the clinician communication of biomarker testing results. Upon receipt of biomarker test results, respondents’ feelings improved (30%,18%), did not change (63%, 55%) or worsened (7%, 27%) about treatment options and prognosis, respectively. Test results made 51% feel more confident in their care, and reduced stress for 25%, but increased stress for 39%, with 1/3 citing sub-par communication of results as at least partly driving the stress increase. The value of clear communication was evident, as the most appealing sample provider statements on results with no actionable biomarkers included confirmation of proposed treatment plan and clarity on non-actionable biomarkers. Not surprisingly, 58% learned the most about their biomarker results from COLONTOWN. Conclusions: Our survey highlights the gaps in communication of biomarker testing results and provides insights on what may improve them. The perceived value of biomarker test results for patients seem to go beyond actionability as traditionally defined. Context-specific, nuanced communication of “what the results really mean” and a discussion of its impact on patient experience needs to be part of clinician communication of test results. We plan to develop resources to help, and we implore clinicians and testing companies to consider our findings and make changes in how they share test results with patients.

Piezoelectric‐Augmented Thermoelectric Ionogels for Self‐Powered Multimodal Medical Sensors (Adv. Mater. 6/2025)

Enhanced Cooperative Generalized Compressive Strain and Electronic Structure Engineering in W‐Ni ₃ N for Efficient Hydrazine Oxidation Facilitating H ₂ Production

Abstract As promising bifunctional electrocatalysts, transition metal nitrides are expected to achieve an efficient hydrazine oxidation reaction (HzOR) by fine‐tuning electronic structure via strain engineering, thereby facilitating hydrogen production. However, understanding the correlation between strain‐induced atomic microenvironments and reactivity remains challenging. Herein, a generalized compressive strained W‐Ni 3 N catalyst is developed to create a surface with enriched electronic states that optimize intermediate binding and activate both water and N 2 H 4 . Multi‐dimensional characterizations reveal a nearly linear correlation between the hydrogen evolution reaction (HER) activity and the d‐band center of W‐Ni 3 N under strain state. Theoretically, compressive strain enhances the electron transfer capability at the surface, increasing donation into antibonding orbitals of adsorbed species, which accelerates the HER and HzOR. Leveraging both compressive strain and the modified electronic structure from W incorporation, the W‐Ni 3 N catalysts demonstrate outstanding bifunctional performance, achieving overpotentials of 46 mV for HER at 10 mA cm −2 and 81 mV for HzOR at 100 mA cm −2 . Furthermore, W‐Ni 3 N catalyst achieves efficient overall hydrazine splitting at a low cell voltage of 0.185 V for 50 mA cm −2 , maintaining stability for ≈450 h. This work provides new insights into the dual engineering of strain and electronic structure in the design of advanced catalysts.

CD8 ⁺ T cell proximity analysis of the tumor microenvironment (TME) in patients with pancreatic ductal adenocarcinoma (PDAC) and associated clinical outcomes.

754 Background: Immunosuppressive cells (cancer-associated fibroblasts [CAFs], tumor associated neutrophils [TANs], M2/M1 macrophages) can influence CD8 + T cell infiltration in the PDAC TME. The spatial proximity of these cells to CD8 + T cells and association with clinical outcomes is not well known. We hypothesize the cell distances between CD8 + T cells and these phenotypes: CXC chemokine receptor 4 (CXCR4) + TANs, CAFs, focal adhesion kinase (FAK) + tumor cells, FAK + M2 and M1 macrophages will correlate with survival outcomes. Methods: Twenty-two stage I/II PDAC patients who consented for tissue collection were stratified into two groups: standard responders (n=11) with overall survival (OS) &gt;2 years and poor responders (n=11) with OS ≤ 2 years. Multiplex IHC was performed on specimens using multiple biomarkers (CD8, CXCR4, CD66b, FAK, FAP, CD68, CSF1R, CD163, EPCAM) to identify cell phenotypes. Comprehensive spatial analysis with HALO software was used to measure mean cell distance between CD8 + T cells and other cells. The mean cell-to-cell distance among evaluable specimens was determined by phenotype. Patients were divided into two groups with average cell distance below or above the mean by phenotype. OS of each subgroup was compared using Kaplan-Meier method. Results: Median OS for standard and poor responders was 47.6 months vs 13.1 months (p&lt;.0001), respectively. There was a higher % of CD8 + T cells closer (&lt;50 µm) to CXCR4 + TANs in standard responders (56% vs 28%, p&lt;.0001). There were no significant differences in CD8 + T cell distance to other phenotypes. Longer survival was seen with average cell distance below the mean when comparing CD8 + T cells to FAK + tumor cells (1274 d vs 742 d, p=.306), to CXCR4 + TANs (854 d vs 442 d, p=.947) and to FAP + FAK + CAFs (890.5 d vs 672 d, p=.662). In contrast, longer survival was seen with a distance above the mean comparing CD8 + T cells to M2 (622 d vs 1274 d, p=.732) and to M1 (613 d vs 1397 d, p=.517) macrophages. Conclusions: Our study shows clinical outcomes may be correlated with spatial distance among TME immune cells in PDAC. Longer survival was seen when CD8 + T cells were closer to FAK + tumor cells, CXCR4 + TANs, and CAFs and further away from M2 and M1 macrophages. Larger cohort analyses may better elucidate the prognostic and biological significance of cell distance among TME phenotypes, which may have potential implications for response to immunotherapy.