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Neoadjuvant and adjuvant pembrolizumab (pembro) plus standard of care (SOC) for resectable locally advanced head and neck squamous cell carcinoma (LA HNSCC): Efficacy by surgical outcomes in the phase 3 KEYNOTE-689 trial.

6057 Background: In the phase 3 KEYNOTE-689 trial (NCT03765918), neoadjuvant and adjuvant pembro plus SOC (surgery and postoperative [chemo]radiotherapy) significantly improved EFS versus SOC in participants (pts) with resectable LA HNSCC. We present results from an exploratory analysis of EFS by surgical outcomes in KEYNOTE-689. Methods: Adults with newly diagnosed resectable LA HNSCC were randomly assigned to receive 2 cycles neoadjuvant pembro 200 mg followed by surgery and 15 cycles adjuvant pembro starting concurrently with postoperative (chemo)radiotherapy (pembro arm) versus surgery and postoperative (chemo)radiotherapy only (control arm). This exploratory analysis evaluated EFS in pts with R0 resection (negative [≥5mm] or close [1-5mm] margin) by local assessment, and postoperative presence or absence of extranodal extension (ENE) or positive (<1mm) surgical margins by BIPR in the PD-L1 CPS ≥1 and total populations of the study. Median study follow-up (data cutoff date: July 25, 2024) was 38.3 months (range, 9.0-66.5). Results: Of 714 total pts, 630 underwent surgery (n = 322, pembro arm; n = 308, control arm). Among 630 who underwent surgery, 307 in the pembro arm and 294 in the control arm had tumors with PD-L1 CPS ≥1. EFS in subgroups by surgical outcome is shown in the table. Conclusions: In this exploratory analysis of the KEYNOTE-689 study, EFS benefit with neoadjuvant and adjuvant pembro added to surgery and postoperative (chemo)radiotherapy occurred in all subgroups by surgical outcome, consistent with the primary analysis population. Fewer pts in the pembro arm had ENE or positive margins post-surgery indicating downstaging due to neoadjuvant pembro. ENE presence or positive margins were associated with a poorer EFS prognosis; however, EFS was better in the pembro arm vs control in pts with or without these high-risk pathological features. Results further support the addition of neoadjuvant and adjuvant pembro to SOC for resectable LA HNSCC. Clinical trial information: NCT03765918 . R0 by local assessment ENE present by BIPR ENE absent by BIPR Positive surgical margins by BIPR Negative surgical margins by BIPR All pts Pembron = 287 Controln = 261 Pembron = 82 Controln = 112 Pembron = 228 Controln = 188 Pembron = 64 Control n = 92 Pembron = 249 Control n = 209 Median EFS, mo NR 40.2 25.2 12.6 NR 57.0 50.3 13.8 NR 51.5 HR (95% CI) 0.67 (0.50-0.88) 0.77 (0.52-1.15) 0.74 (0.53-1.05) 0.58 (0.36-0.93) 0.78 (0.57-1.07) 36-mo rate, % 64.0 51.1 41.3 33.8 68.4 58.5 58.0 36.8 63.0 55.6 CPS ≥1 Pembron = 275 Controln = 249 Pembron = 76 Controln = 109 Pembron = 220 Control n = 178 Pembron = 58 Control n = 89 Pembron = 242 Controln = 198 Median EFS, mo NR 35.3 25.2 12.6 NR 57.0 50.3 13.8 NR 50.1 HR (95% CI) 0.62 (0.47-0.83) 0.74 (0.49-1.12) 0.71 (0.51-1.01) 0.60 (0.37-0.98) 0.72 (0.53-1.00) 36-mo rate, % 65.1 49.5 42.3 33.9 68.5 56.6 55.0 36.0 64.2 53.9

Racial disparities in stage at diagnosis of HIV–associated cancers: A SEER Analysis 2018-2022.

e13733 Background: Cancer risk is increased in people living with HIV (PLWH), and malignancy forms a leading cause of morbidity and mortality in this population. Multiple cancers are known to be associated with HIV/AIDS, including NHL, Hodgkin Lymphoma, Kaposi Sarcoma and cancers of the genital tract. Concurrently, patients with HIV are known to have worse outcomes following a cancer diagnosis, partially due to inequities in receipt of treatment. In this study, we examined racial differences in stage at diagnosis of HIV-associated cancers, including comparing to Colorectal cancer, a cancer of significant incidence and established surveillance paradigms. Methods: We conducted a population-based cohort study of patients diagnosed with HIV-associated cancers in the United States. We queried the National Cancer Institute Surveillance, Epidemiology and End Results Program (SEER) from 2018-2022. Age-adjusted incident rates (AAIRs) were calculated per 1,000,000 population for each race using the direct standardization method based on age group weights from the 2000 standard US population. Stage was defined by the Summary Stage 2018 categories. Distribution of stage at diagnosis within racial groups were calculated as percentages. Differences in stage distribution were assessed using the chi-square test, with effect size quantification using Cramér’s V. Multivariable logistic regression was performed to evaluate association between race and distant stage at diagnosis while adjusting for age, household income and rurality. Comparisons with colorectal cancer were based on published national stage distributions. Results: A total of 126,206 cancer cases were identified. Across all racial groups, the highest AAIRs were observed for distant disease, with greatest burden observed among Hispanic (5.94) and lowest among Asian/Pacific Islander patients (4.13). A substantial proportion of all racial groups presented with advanced disease at diagnosis (Hispanic 41.3%, White 43.8%, Black 40.9%, Asian or Pacific Islander 42.1%, American Indian/Alaska Native 42.1%). While on unadjusted analysis stage at diagnosis differed significantly by race (χ² = 216.5, df = 8, p < 0.001), the magnitude of association was small (Cramér’s V = 0.029), and after adjustment race was not found to be independently associated with distant stage disease at diagnosis (adjusted OR 1.02(0.99-1.04) p = 0.19). Conclusions: While race was not found to correlate with distant disease independently, almost half of our studied cancers were found to be advanced stage at diagnosis. In comparison, only 22.5% of colorectal cancer cases were advanced at diagnosis. It is possible that systemic and structural barriers may play a role in patients with cancers classically associated with HIV being unable to obtain timely care across all races. Tailored screening and surveillance programs may be warranted to promote earlier diagnosis of cancer among PLWH.

ALKOVE-1: Efficacy and safety of neladalkib in patients with advanced <i>ALK</i> + NSCLC.

8503 Background: Neladalkib is an investigational ALK TKI designed for inhibition of ALK single and compound resistance mutations, brain penetrance, and sparing TRK. We report the first analyses of phase 2 TKI pre-treated patients (pts) and preliminary data in TKI-naïve pts with ALK + NSCLC . Methods: The global, single arm phase 1/2 ALKOVE-1 trial (NCT05384626) enrolled pts with advanced/metastatic ALK + NSCLC. Key study endpoints are objective response rate (ORR, RECIST v1.1 by BICR), duration of response (DOR), intracranial ORR (IC-ORR) and safety. Efficacy analyses included TKI pre-treated pts who initiated neladalkib 150 mg QD by 30 Sep 2024 or all treated TKI-naïve pts. Data cut: 29 Aug 2025. Results: 656 pts with ALK + NSCLC received neladalkib. Efficacy-evaluable TKI pre-treated pts (n=253) had received a median of 3 prior anticancer therapies (range 1-11, 51% prior chemo). 78% of pts received ≥2 (range 2-5) prior ALK TKIs, of whom 91% had prior lorlatinib. 19% had single or compound ALK G1202R resistance mutations. 40% had CNS disease by BICR. ALK TKI pre-treated results are reported in the Table. In a preliminary analysis of TKI-naïve pts, ORR was 86% (38/44, 2 uPRs); 12-month DOR rate was 91%. IC-ORR was 78% (7/9) with no CNS progression events as of data cutoff. Conclusions: In this ALK TKI pre-treated data set, neladalkib demonstrated clinically meaningful activity, including in pts with CNS disease, ALK G1202R single or compound mutations, and prior lorlatinib. Encouraging preliminary activity was also observed in TKI-naïve pts. Neladalkib’s safety profile was consistent with its ALK-selective, TRK-sparing design. Clinical trial information: NCT05384626 . Efficacy Parameter (RECIST v1.1, BICR) All ALK TKI Pre-treated± chemo ALK TKI Pre-treated,Lorlatinib-naïve ± chemo ORR % (n/N)95% CI 31 (79/253) a, b 26, 37 46 (29/63) c 33, 59 % DOR ≥ 12 m (95% CI) / 18 m (95% CI) d 64 (51, 75) / 53 (34, 68) 80 (58, 91) / 60 (19, 85) G1202R Mutation ORR % (n/N)95% CI 68 (32/47) e,f 53, 81 83 (10/12)52, 98 % DOR ≥ 12 m d (95% CI) 80 (61, 91) 77 (34, 94) Intracranial Activity IC-ORR % (n/N)95% CI 32 (29/92) g, h 22, 42 63 (15/24) g 41, 81 % IC-DOR ≥ 12 m d (95% CI) 71 (48, 85) 92 (57, 99) m, months; NE, not estimable. a Includes 2 unconfirmed partial responses (uPRs). b Pts with prior lorlatinib: ORR 26% (50/190, including 2 uPRs) and mDOR 17.6 m (95% CI: 6.9, NE). c Pts with 1 prior 2 nd generation ALK TKI (alectinib, n=44; brigatinib, n=2) ± chemo: ORR 48% (22/46) and DOR ≥ 12 m of 74% (95% CI: 48, 88). d Estimated by Kaplan-Meier analysis. e Single or compound G1202R resistance mutations may be present. f Includes 1 uPR. g Includes 2 IC-uPRs. h Pts with prior lorlatinib: IC-ORR 21% (14/68) and IC-DOR ≥ 12 m of 55% (95% CI: 26, 77).

Stereotactic body radiotherapy (SBRT) combined with PD-1 inhibitor and chemotherapy in early-stage treatment-naive triple-negative breast cancer patients: A multicenter phase III clinical study.

TPS657 Background: Early-stage triple-negative breast cancer (TNBC) carries a high risk of locoregional recurrence and distant metastasis. The KEYNOTE-522 trial established that adding an immune checkpoint inhibitor to neoadjuvant chemotherapy in high-risk early-stage TNBC yields a pathologic complete response (pCR) rate of 64.8%. However, nearly 40% of patients still fail to achieve pCR. Radiotherapy not only directly eradicates tumor cells but also can induce systemic immunomodulatory effects, such as promoting tumor antigen release and enhancing T-cell infiltration. Therefore, combining radiotherapy with immune checkpoint inhibitors and chemotherapy represents a promising strategy to improve outcomes in early-stage TNBC. Preliminary data from small-sample, single-arm studies suggest that neoadjuvant stereotactic body radiotherapy (SBRT) combined with an anti-PD-L1 antibody and chemotherapy can increase pCR rate to 90%(Liu C., et al., Elife , 2023). However, this therapeutic modality lacks large-scale clinical data to further confirm the radiosensitizing effect of radiotherapy on immune checkpoint inhibitors. This phase III, randomized, controlled, multicenter study aims to evaluate the efficacy and safety of toripalimab (an anti-PD-1 monoclonal antibody) plus chemotherapy with or without SBRT in treatment-naïve TNBC patients. Methods: Eligible patients are treatment-naïve, non-metastatic TNBC with clinical stage cT1cN1-2M0 or cT2N0-2M0 (AJCC 8th edition). Patients are randomized 1:1 to receive toripalimab (240 mg, intravenously, every 3 weeks for 8 cycles) plus nab-paclitaxel (260 mg/m², intravenously, every 3 weeks for cycles 1-4) and carboplatin (AUC=5, intravenously every 3 weeks for cycles 1-4) and epirubicin (90-100 mg/m², intravenously, every 3 weeks for cycles 5-8) and cyclophosphamide (600 mg/m², intravenously every 3 weeks for cycles 5-8), with or without SBRT (8 Gy × 3 fractions). All patients undergo surgery 4-8 weeks after completing neoadjuvant therapy. The primary endpoint is investigator-assessed pCR. Secondary endpoints include breast conservation rate, ipsilateral breast recurrence or locoregional recurrence, overall survival (OS), and safety. Sample size was calculated assuming a pCR rate of 64.8% in the control arm (based on KEYNOTE-522) and 80% in the experimental (SBRT) arm. With a one-sided α of 0.025, 80% power, 1:1 allocation, and accounting for a 20% dropout rate, 159 patients per arm (total N=318) are enrolled. The study was initiated in November 2024. Clinical trial information: NCT06627712 .

Second locoregional recurrence (LRR) in hormone receptor (HR)+/HER2- breast cancer (BC).

e12537 Background: Evidence regarding the treatment and prognosis of patients with HR+/HER2- BC who experience a second consecutive, ipsilateral LRR remains limited. Methods: We analyzed treatment patterns and clinical outcomes of patients (pts) with HR+/HER2- BC who experienced a second consecutive, ipsilateral LRR, after a prior radical surgery and/or radiation therapy, with or without systemic treatment, and underwent surgery (study baseline) at the European Institute of Oncology (Milan) from Jan 2001 to Sep 2025 (cohort study). Patients with bilateral invasive BC, contralateral invasive recurrence, a non-invasive ipsilateral event before baseline, or a tumor clinical subtype switch were excluded. Endpoints included invasive breast cancer-survival (IBCFS) and distant recurrence-free survival (DRFS). Results: A total of 111 pts were included. The median age at study baseline was 61 years (IQR: 52-68), 77% were postmenopausal. The second LRR occurred in the residual breast parenchyma in 44% of pts, in locoregional lymph nodes in 23%, on the mastectomy scar or chest wall in 31%, and at multiple sites in 2%. An endocrine-resistant recurrence according to ESMO guidelines was observed in 69% of pts. ‘Adjuvant’ chemotherapy was administered in 14% of pts, and 5% received a CDK4/6 inhibitor. Endocrine therapy consisted predominantly of aromatase inhibitors (82%), with a switch from nonsteroidal to steroidal agents in 69% of these patients; fulvestrant was prescribed in 14%, tamoxifen in 2%, and no endocrine therapy in 2%. At a median follow-up of 6.3 years, 58 IBCFS and 37 DRFS events were reported. The median IBCFS was 6.8 years (95%CI: 5.0-8.6) and DRFS 13.5 years (95%CI: 6.3-20.7). A longer median DRFS was reported in pts with endocrine-sensitive LRR (not reached [NR] vs. 7.6 years in case of endocrine-sensitive LRR; p = .027) and in pts with LRR in breast tissue vs. those with lymph nodal or chest wall recurrence (NR vs. 9.0 vs. 5.5 years; p = .018). Conclusions: In this analysis, pts with a second consecutive HR+HER2- LRR who have endocrine-sensitive, intraparenchymal breast disease had favorable outcomes without chemotherapy. Those with endocrine-resistant disease or chest wall/lymph node recurrence had poorer outcomes and may warrant treatment intensification.

Trends and disparities in mortality related to malignant genital neoplasms in the United States, 1999-2023.

e23361 Background: Malignant genital neoplasms in both men and women markedly elevate mortality risk, as tumor progression and reproductive organ compromise intensify systemic vulnerability. This study aims to analyze and interpret trends, geographic variations, and disparities among men and women in the United States. Methods: The mortality data from the CDC WONDER multiple cause of death files for all ages were used to analyze age-adjusted and crude mortality rates (AAMRs and CMRs) per 100,000 through ICD-10 Codes: C51–C58 for female genital cancer and ICD-10 Codes: C60–C63.9 for male genital cancer, stratified by year, gender, race/ethnicity, place of death and geography. Joinpoint regression was used to estimate average annual percent change (AAPC) with 95% confidence intervals (CIs). Statistical significance was defined as p &lt; 0.05. Results: A total of 1,907,686 deaths were attributed to patients with malignant genital neoplasms (females: 812,497; males: 1,095,189), with most occurring at the decedent's home (40.76%). The overall AAMR declined from 27.48 in 1999 to 20.64 in 2023 (AAPC: –1.22; 95% CI: –1.51 to –0.93; p &lt; 0.000001), with a significant decline observed between 1999–2013 (APC: –2.15; p &lt; 0.000001), followed by a significant rise between 2018–2021 (APC: 2.39; p = 0.019). Men had higher AAMR (33.03 vs 17.07), but the decline in mortality was more pronounced than among women (AAPC: –2.08 vs –0.55). Older adults aged ≥65 years had the highest CMR among other age groups (201.55). By race, the highest AAMR was noted among non-Hispanic (NH) Blacks (35.69), while the lowest was among NH Asians (11.76). Geographic disparities were evident, with the Midwest having the highest AAMR and the South having the lowest (22.94 vs 22.11). Non-metropolitan areas showed higher AAMR than metropolitan areas (23.77 vs 22.46). A steeper decline in mortality was seen in metropolitan areas compared to non-metropolitan areas (AAPC: -1.45 vs -1.38). At the state level, the District of Columbia ranked highest, placed in the top 90th percentile from 1999 to 2023. Conclusions: Mortality from malignant genital neoplasms has declined over the past two decades, with a disproportionate impact on older adults, men, NH Blacks, and the population of non-metropolitan and Midwest regions. Targeted interventions and equitable access to healthcare are needed to reduce mortality and address persistent health inequities among vulnerable populations. Average annual percent change (AAPC) of age-adjusted mortality rates for malignant genital neoplasms in the United States, 1999 to 2023. Variable Deaths AAPC (95%CI) Overall 1,907,686 -1.22 (-1.51 to -0.93) Male 1,095,189 -2.08 (-2.50 to -1.66) Female 812,497 -0.55 (-0.70 to -0.40) Non-metropolitan areas 303,668 -1.38 (-1.63 to -1.13) Metropolitan areas 1,340,710 -1.45 (-1.62 to -1.29)

Safety and feasibility of cabozantinib (CABO) in combination with cisplatin, doxorubicin, and high-dose methotrexate (MAP) in patients with newly diagnosed high-risk osteosarcoma (OS).

10030 Background: CABO is a multi-targeted kinase inhibitor of VEGFR2, c-MET, AXL and RET and has shown clinical evidence of activity in two prior studies of adult and pediatric patients with advanced OS. We report results of a feasibility cohort of CABO + MAP chemotherapy in patients with newly diagnosed high-risk OS. Methods: Patients &lt;40 years, body surface area ≥ 0.8 m 2 and new diagnosis of high-grade OS with metastatic disease and resectable primary tumor were eligible. Patients were enrolled to two CABO dose levels (Dose Level 1 (DL1) 25 mg/m 2 /day, maximum 40 mg/day; Dose Level 2 (DL2) 35 mg/m 2 /day; maximum 60 mg/day) using a modified IQ 3+3 design. CABO was orally administered concomitantly with six 35-day cycles of MAP (cisplatin 60 mg/m 2 on days 1-2 (cycles 1-4), doxorubicin 37.5 mg/m 2 on days 1-2 (with dexrazoxane), methotrexate 12 g/m 2 on days 22, 29) and for 24 weeks as maintenance monotherapy. CABO was held after 7 weeks and resumed during 4 th MAP cycle to allow for primary tumor resection and metastatic surgeries. Dose-limiting toxicities (DLT) were assessed during weeks 1-6 of treatment; additional monitoring for post-surgical complications was conducted through completion of 4 th MAP cycle. The primary endpoint for this cohort was feasibility of combination therapy. Results: Ten patients (median age 11.5 years, 70% male) were enrolled and treated with CABO + MAP (DL1, n=4; DL2, n=6). Median cumulative doses of all MAP agents were maintained throughout treatment with no dose reductions. Concomitant dosing of CABO with MAP was tolerated with no protocol-specified DLTs occurring during the evaluation period. DL2 (35 mg/m 2 ) was established as the recommended dose for further study of combination therapy. Commonly reported adverse events included hematologic toxicities, febrile neutropenia, and alanine/aspartate aminotransferase (AST/ALT) elevation. Interruption of CABO was required in 6 patients for Grade 3+ AST/ALT elevation following methotrexate (n=3), wound complications (n=3), and Grade 3 pneumothorax (n=1). Wounds included two Grade 3 port site events and one Grade 1 primary tumor resection site; two patients later resumed CABO after healing without wound recurrence. Dose reduction of CABO was required in one patient for Grade 4 amylase elevation. Conclusions: The combination of CABO + MAP is feasible with no protocol-specified DLTs during the evaluation period. Generalizability is limited based on cohort size. Further evaluation of CABO + MAP is ongoing in a phase II/III randomized efficacy study in newly diagnosed standard and high-risk patients using CABO dose of 35 mg/m 2 /day (max 60 mg), with delayed initiation of CABO in patients with port placement and early safety monitoring for wound-related events, as well as full study monitoring of dose delivery, wound complications and systemic toxicity. Clinical trial information: NCT05691478 .

Survival outcomes of plasmablastic lymphoma according to immune status.

7088 Background: Plasmablastic lymphoma (PBL) is a rare, aggressive subtype of NHL associated with HIV, but also reported in other immunosuppressed states. Outcomes of PBL patients with non–HIV-related immunosuppression remain poorly defined. We compared clinicopathological features and survival outcomes among patients with HIV-associated immunosuppression (IS-HIV), and non–HIV-related immunosuppression (IS) and those without HIV or history of immunosuppression (IC). Methods: We retrospectively analyzed 35 patients with pathologically confirmed PBL, including 14 IC, 16 IS-HIV, and 5 IS patients. Associations between immune status and clinical characteristics were assessed using chi-square analysis. Progression-free survival (PFS) and overall survival (OS) were evaluated using Kaplan–Meier analysis with log-rank testing and multivariable Cox proportional hazards regression. Results: Median ages were 49, 45, and 56 years for IC, IS-HIV, and IS groups, with male predominance across all groups (71.4%, 93.8%, and 100%), respectively. Epstein–Barr virus positivity was significantly higher in IS-HIV (93.8%) and IS (40.0%) compared with IC patients (14.3%; p &lt; 0.01). IS patients had lower rates of extranodal involvement than IC and IS-HIV patients (80.0% vs 100%; p = 0.04). Immune status was not associated with age, sex, ethnicity, ECOG performance status, stage, IPI score, radiation therapy, CNS prophylaxis, or autologous stem cell transplantation. Rates of primary refractory disease and relapse did not differ significantly among IC (14.3%, 21.4%), IS-HIV (31.3%, 12.5%), and IS (40.0%, 0%) groups (p = .42 and p = .48, respectively). Response rates following first-line therapy were numerically lower in IS patients but did not differ significantly ( p = 0.23). Median follow-up was 30, 21, and 4 months for IC, IS-HIV, and IS groups, respectively. Median PFS was 60.5 months, not reached, and 4 months for IC, IS-HIV, and IS groups, respectively ( p = 0.03). One- and two-year OS rates were 78.6% and 64.3% (IC), 74.0% and 65.8% (IS-HIV), and 0% and 0% (IS; p = 0.02). On multivariable analysis, IS status was associated with inferior PFS (HR 3.6, p = 0.03) and OS (HR 3.9, p = 0.03), whereas IS-HIV was not. Conclusions: PBL patients with non–HIV-related immunosuppression experienced significantly inferior PFS and OS compared with IC and IS-HIV patients. Although lower response rates and higher primary refractory disease were observed in IS patients, these differences did not reach statistical significance, likely due to small sample size. Consistent with prior reports, HIV-associated immunosuppression was not associated with worse survival. Larger studies are needed to better define disease biology and optimize therapeutic strategies for this high-risk population.

Smart drug nanoparticles from microbes and their drug delivery

High‐Efficiency Organic Solar Cells Enabled by Siloxane‐Functionalized Pyrazine Terpolymers: Synergizing Performance, Morphology Control, and Non‐Halogenated Solvent Processability

ABSTRACT Balancing high performance, morphological controllability, and compatibility with non‐halogenated solvent processing remains a critical bottleneck for scalable and sustainable organic solar cells (OSCs). Herein, we address this challenge via rational terpolymer design: integrating a siloxane‐functionalized electron‐deficient pyrazine unit (DTCPz‐SiO) into the benchmark D18 backbone, with the optimized terpolymer DN1 containing 5 mol% DTCPz‐SiO. DTCPz‐SiO imparts two key synergies: (i) enhanced conformational rigidity and intramolecular noncovalent interactions (N···S, N···H), which improve backbone planarity, strengthen π–π stacking, and accelerate crystallization; (ii) synergistic regulation of donor‐acceptor miscibility and compatibility with non‐halogenated solvents. These effects collectively enable a well‐optimized bulk‐heterojunction morphology with enhanced molecular ordering and charge dynamics. Consequently, DN1‐based binary devices deliver a significantly improved power conversion efficiency (PCE) of 20.1% compared to 18.7% for the parent polymer, together with a broadened processing window. Notably, high efficiencies of ∼19.5% are retained under common non‐halogenated processing conditions. Furthermore, DN1‐based ternary OSCs enhance PCE to outstanding values of 20.9% and 20.0% under chlorinated and non‐halogenated processing conditions, respectively, among the highest efficiencies reported for single‐junction OSCs. Overall, this work establishes siloxane‐functionalized terpolymers as an effective molecular design strategy for regulating multi‐scale morphology and processing tolerance, providing new insights for the development of scalable OSC systems.

Phase II RAINSPOT: A multicentric open label trial of zolbetuximab-paclitaxel-ramucirumab in second-line setting for CLDN18.2-positive gastro-esophageal adenocarcinoma.

TPS4243 Background: Claudin 18.2 (CLDN18.2) is an emerging therapeutic biomarker in gastro-oesophageal adenocarcinoma. Phase III trials (SPOTLIGHT, GLOW) showed significant overall survival (OS) and progression-free survival (PFS) benefit from adding zolbetuximab to first-line chemotherapy. However, access to zolbetuximab remains limited in Belgium due to lack of reimbursement, and globally for patients receiving immunotherapy first line. Aim: RAINSPOT (NCT06962137) evaluates the efficacy and safety of adding zolbetuximab to standard second-line paclitaxel–ramucirumab in CLDN18.2-positive advanced gastro-oesophageal adenocarcinoma. Secondary objectives include assessing CLDN18.2 expression loss after first-line progression and evaluating zolbetuximab efficacy according to maintained versus lost CLDN18.2 expression. Methods: RAINSPOT is a national, multicentre, phase II, open-label study with a prospective single-arm cohort and a matched retrospective cohort across six Belgian centres. The prospective cohort will include 100 patients (≥18 years, ECOG 0–1) with metastatic or locally advanced disease progressing after one prior systemic line. Tumours must be CLDN18.2-positive (≥75% moderate-to-strong membranous staining; Ventana 43-14A assay). A fresh biopsy at progression is obtained when feasible. Treatment consists of zolbetuximab (800 mg/m² loading, then 400 mg/m² q2w), paclitaxel (80 mg/m² weekly ×3 q28d) and ramucirumab (8 mg/kg q2w). Treatment continues until progression or unacceptable toxicity. HRQoL is assessed every 4 weeks (EORTC QLQ-C30, QLQ-OG25). The retrospective cohort includes patients treated with second-line paclitaxel–ramucirumab (2021–2023) with archived tissue reassessed for CLDN18.2; only baseline-positive patients are eligible. Propensity score matching (1:1; SMD ≤0.05) uses age, sex, tumour location, gastrectomy, peritoneal metastases and centre. This study is supported by Astellas. Results: (Trial in Progress) Enrollment began December 2025 and will continue for 24 months, with 24 months’ follow-up. Planned analyses include OS, PFS, objective response rate, toxicity and HRQoL. Conclusion: RAINSPOT is the first study evaluating zolbetuximab plus paclitaxel–ramucirumab in second-line CLDN18.2-positive gastro-oesophageal adenocarcinoma. By integrating a matched real-world comparator, it aims to generate near-randomized evidence on survival, tolerability and quality of life, informing optimal treatment sequencing. Clinical trial information: NCT06962137 .

Clinicopathologic characteristics and treatment outcomes of advanced high-grade serous ovarian cancer in Pakistan: A single-center study.

e17553 Background: High-grade serous ovarian carcinoma (HGSC) is the most lethal subtype of ovarian cancer. Evidence from low- and middle-income countries remains limited, particularly regarding access to genetic testing and delivery of multimodality care. The purpose of this study was to describe real-world patterns of presentation, treatment, and outcomes of advanced HGSC in a resource-limited setting and to identify gaps relevant to future care improvement. Methods: We conducted a retrospective review of 50 patients with FIGO stage III–IV HGSC treated between 2024 and 2025 at a tertiary care center in Pakistan. Collected variables included age, family history, BRCA1/2 testing status, disease stage, use of neoadjuvant chemotherapy (NACT), surgical intervention, systemic chemotherapy, and documented treatment response. Results: Median age was 50 years (range, 31–65), with 20% of patients aged ≤40 years. Stage III disease was observed in 36% and stage IV in 64%. A positive family history was present in 18%. BRCA testing was performed in only 16%, with pathogenic variants identified in 37.5% of those tested. NACT was administered in 40%, surgery in 70%, and systemic chemotherapy in 84% of patients. Surgical intervention was more frequent in stage III compared with stage IV disease (83% vs 63%), reflecting differences in disease burden at presentation. Among patients with available outcome data, complete response was predominantly observed in stage III disease treated with combined surgery and chemotherapy. Conclusions: Patients frequently presented at a younger age and with advanced-stage HGSC, underscoring delays in diagnosis and referral. Despite resource constraints, meaningful clinical responses were achievable with comprehensive multimodality treatment, particularly in stage III disease. These findings support prioritization of expanded BRCA testing, multidisciplinary treatment pathways, and prospective data collection. Strengthening early detection, genetic risk stratification, and health system capacity may reduce global disparities and improve ovarian cancer outcomes in low-resource settings. Patient characteristics and treatment summary (N = 50). Variable Value Median age, years (range) 50 (31–65) Age ≤40 years 10 (20%) Stage III disease 18 (36%) Stage IV disease 32 (64%) Positive family history 9 (18%) BRCA testing performed 8 (16%) BRCA-positive (of tested) 3 (37.5%) Neoadjuvant chemotherapy 20 (40%) Surgery performed 35 (70%) Systemic chemotherapy 42 (84%)

Correlation between dual FDG/PSMA PET mismatch and ctDNA genomic profiling in metastatic castration-resistant prostate cancer (mCRPC) patients screened for 177Lu-PSMA.

5067 Background: 177Lu-PSMA radioligand therapy is now a standard treatment for patients (pts) with mCRPC. Dual-tracer FDG/PSMA PET imaging mismatch (i.e. FDG+ and PSMA- lesions) is currently the main selection criterion used to predict 177Lu-PSMA response. However, this approach is time-consuming, resource-intensive and may not fully capture tumor biological aggressiveness. More accessible and biologically informative biomarkers are therefore needed. Methods: This retrospective, single-center study included pts diagnosed with mCRPC who underwent FDG and PSMA PET for 177Lu-PSMA screening and circulating tumor DNA next-generation sequencing (ctDNA) as part of the STING program (NCT04932525) at Gustave Roussy. A tumor suppressor gene alterations (TSalt) signature was defined by ≥ 2 alterations among TP53, PTEN and/or RB1 . Univariate logistic and linear regression models were used along with area under the curve (AUC) to assess associations between genomic and mismatch as well as PET-derived parameter. Progression-free survival (PFS, PCWG3 criteria) and overall survival (OS) were analyzed using univariate Cox models. Results: Among the 110 pts with available ctDNA and dual-tracer imaging, 18 (16.4%) exhibited mismatch. TSalt+ tumors were identified in 24 pts (21.8%) and were enriched in the mismatch group (50.0 vs 16.3%, p = 0.004) and in case of liver metastases (33.3% vs 10.5%, p = 0.011). TSalt was associated with mismatch (p = 0.003, AUC = 0.625). TSalt predicted higher total lesion glycolysis (TLG; p &lt; 0.001, AUC = 0.720), increased ratio TLG/total lesion activity (TLA; p = 0.008, AUC = 0.657), larger FDG+ tumor volume (p = 0.008, AUC = 0.720), and lower PSMA+ tumor volume (p &lt; 0.001, AUC = 0.725). TSalt+ pts had significantly shorter OS compared with TSalt- pts (median 5.7 vs 16.5 months; HR 3.31, 95% CI [1.93–5.69], p &lt; 0.001). Similarly, pts with mismatch had inferior OS (median 4.7 vs 16.3 months; HR 3.17, 95% CI [1.69–5.95], p &lt; 0.001). Among the 79 pts treated with 177Lu-PSMA, TSalt+ status (n = 14, 17.7%) was associated with shorter median PFS (3.5 vs 5.1 months; HR 2.37, 95% CI [1.29–4.34], p = 0.004) and OS (5.5 vs 15.3 months; HR 4.19, 95% CI [2.17–8.10], p &lt; 0.001). Patients with mismatch (n = 3, 3.8%) also experienced inferior outcomes, with shorter PFS (2.5 vs 4.9 months; HR 3.80, 95% CI [1.14–12.7], p = 0.02) and OS (5.6 vs 15.1 months; HR 4.97, 95% CI [1.48–16.7], p = 0.004). Conclusions: The TSalt genomic signature was associated with FDG/PSMA PET mismatch, adverse metabolic imaging features, and poorer survival in patients with mCRPC, including those treated with 177Lu-PSMA. These findings suggest that ctDNA genomic profiling may help identify molecular imaging mismatch, associated with biologically aggressive disease, such as lineage plasticity phenotypes. Prospective studies are warranted to validate its clinical utility.

FGF4-mediated resistance to combined anti-angiogenic and immunotherapy in esophageal squamous cell carcinoma via suppression of high endothelial venules and tertiary lymphoid structure formation.

4077 Background: Many patients with locally advanced esophageal squamous cell carcinoma (LA-ESCC) fail to achieve a pathological complete response (pCR) following neoadjuvant immunochemotherapy plus anti-angiogenic therapy, which is associated with a poor prognosis. The identification of predictive biomarkers and the elucidation of resistance mechanisms constitute a major challenge. This study aims to identify relevant biomarkers and elucidate the underlying mechanisms to improve therapeutic outcomes. Methods: Exploratory analyses were conducted on 70 untreated LA-ESCC patients from a phase II clinical trial (ChiCTR2100051763) treated with two 21-day cycles of neoadjuvant treatment with intravenous camrelizumab (200mg), albumin-paclitaxel (260mg/m 2 ), carboplatin (AUC=5) on day 1, and oral apatinib (250mg) on days 1-14, followed by the third cycle without apatinib. Pre-treatment tumor tissues were subjected to transcriptomic and whole-exome sequencing to identify differential pathways and genetic alterations between patients achieving pCR and non-pCR. Candidate biomarkers were further validated by immunohistochemistry. In vitro and in vivo experiments were employed to elucidate the mechanisms underlying treatment resistance. Results: Pathway analysis identified significant enrichment of the fibroblast growth factor receptor (FGFR) signaling pathway in non-pCR patients, with FGF4 as the most upregulated factor. FGF4 alterations were primarily gene amplifications, occurring in 40% of cases. FGF4 expression predicted treatment resistance (non-pCR) with an AUC of 0.857 (95% CI: 0.744–0.97). Multiplex immunohistochemistry revealed that tumors overexpressing FGF4 exhibited impaired vascular normalization, evidenced by significantly reduced pericyte coverage and basement membrane integrity. These tumors also showed lower densities of high endothelial venules (HEVs), CD8+ T cells, and tertiary lymphoid structures (TLSs) following combination therapy. In vivo experiments confirmed that FGF4 overexpression led to decreased pericyte and basement membrane coverage, reduced HEV density, and diminished CD8+ T cell infiltration. Notably, pharmacological inhibition of FGFR signaling reduced tumor growth and increased the pCR rate, effectively reversing the resistance mediated by FGF4. Conclusions: Aberrant FGF4 expression drives resistance to combined immunochemotherapy and anti-angiogenic therapy by impeding vascular normalization, which subsequently suppresses the formation of HEVs and tertiary TLSs. Targeting FGFRs might be a promising strategy to overcome FGF4-driven treatment resistance in ESCC. Clinical trial information: ChiCTR2100051763.

First-in-human phase 1a/1b study of LB-LR1109, an anti-LILRB1 monoclonal antibody, as monotherapy in advanced solid tumors and in combination with atezolizumab in advanced NSCLC.

TPS2668 Background: LB-LR1109 is a human IgG4 monoclonal antibody targeting LILRB1, an inhibitory receptor expressed on multiple immune cell subsets. LILRB1 binds HLA-G, delivering suppressive signals that enable tumor immune evasion. Blocking this axis may restore immune activation within the tumor microenvironment and promote both innate and adaptive anti-tumor responses. Phase 1a tumor types were selected through TCGA analyses showing high LILRB1/HLA-G expression and increased infiltration of LILRB1+ NK cells, T cells, and monocytes in RCC, NSCLC, HNSCC, urothelial carcinoma (UC), and melanoma. High LILRB1 expression correlates with poor overall survival in RCC, UC, and lung SCC, supporting clinical relevance. Preclinical data (AACR2026 #1243) demonstrated that LB-LR1109 binds LILRB1 with high affinity, blocks HLA-G interactions, restores NK and T-cell function, and induces strong anti-tumor activity in human LILRB1 transgenic mouse models. LB-LR1109 also showed synergy with PD-L1 blockade, favorable PK, and an excellent safety profile, supporting clinical development as monotherapy and in combination. Public transcriptomic data also support combining LB-LR1109 with atezolizumab in NSCLC based on correlated LILRB1 and PD-L1 expression. Methods: This ongoing first-in-human, multicenter, open-label Phase 1 study (NCT06332755) evaluates LB-LR1109 as monotherapy (Phase 1a) and in combination with atezolizumab (Phase 1b). The study began in September 2023; Phase 1b enrollment started December 2025. Phase 1a includes monotherapy dose escalation (DL1–DL8, IV Q2W) using BLRM, enrolling patients with advanced/metastatic RCC, NSCLC, HNSCC, UC, or melanoma who relapsed from or are intolerant to approved therapies. Phase 1b evaluates LB-LR1109 (IV Q2W) plus atezolizumab 840 mg Q2W in advanced/metastatic NSCLC without actionable mutations. Patients must have received prior approved therapies including anti-PD-1/PD-L1 with ≥12 weeks of response, to test whether LILRB1 blockade may restore immune surveillance after checkpoint inhibitor resistance. Primary objectives: safety, tolerability, and determination of MTD/RP2D. Secondary endpoints: antitumor activity, PK, immunogenicity. Exploratory endpoints: correlations between LILRB1/HLA-G expression and clinical response, longitudinal immune profiling, and receptor occupancy in peripheral monocytes. The study is conducted at eight sites in Korea and the United States. Phase 1a has escalated to DL7 with no DLTs, and enrollment into the combination DL5 cohort began January 2026. Clinical trial information: NCT06332755 .

Neoadjuvant chemotherapy with or without radiation versus upfront esophagectomy in small cell carcinoma of the esophagus: A national database analysis of overall survival.

e16126 Background: Small cell carcinoma of the esophagus (SCCE) is a rare malignancy characterized by aggressive biology, with most patients presenting with metastatic disease. For patients with locoregional disease, esophagectomy is commonly performed; however, the role of neoadjuvant chemotherapy with or without radiation remains unclear, and no standard treatment approach has been established. Methods: The United States National Cancer Database was queried for adults diagnosed with esophageal cancer between 2004 and 2023. Patients with pathologically confirmed small cell neuroendocrine carcinoma of the esophagus without metastatic disease were identified. Patients were grouped by treatment strategy: upfront esophagectomy or neoadjuvant chemotherapy with or without radiation followed by surgery. Demographic and clinical characteristics were compared using Wilcoxon rank-sum and Fisher’s exact tests. Overall survival (OS) was estimated using Kaplan–Meier methods and compared using the log-rank test. Multivariable Cox proportional hazards regression was used to assess the association between treatment strategy and OS, adjusting for age and Charlson–Deyo Comorbidity Index (CDCC). Results: A total of 114 patients were included; 86% were White, 8% Black, and 6% were of other racial or ethnic groups. Fifty-nine patients (51.7%) received neoadjuvant therapy, while 55 (48.3%) underwent upfront esophagectomy. Most patients (74.5%) had a CDCC score of 0. Patients receiving neoadjuvant therapy were significantly younger than those undergoing upfront surgery (median age 59.2 vs 66.2 years, p &lt; 0.001). Neoadjuvant chemotherapy with or without radiation was associated with significantly improved OS compared with upfront esophagectomy (median OS 28.6 vs 14.1 months; log-rank p = 0.04). On multivariable analysis, upfront esophagectomy demonstrated a non-significant trend toward higher mortality (HR 1.22; 95% CI 0.65–2.28; p = 0.54), while increasing age was independently associated with worse OS. Conclusions: In this retrospective national cohort of patients with non-metastatic SCCE, neoadjuvant chemotherapy with or without radiation was associated with improved overall survival compared with upfront esophagectomy. These findings support consideration of neoadjuvant therapy in the management of locoregional SCCE. Treatment group Median OS (months) (95% CI) Log-rank P Neoadjuvant treatment- chemotherapy/radiation 28.62 (20.44-73.30) 0.04 Upfront esophagectomy 14.13 (11.17-40.61)

Patterns of health information seeking and digital health engagement in adults with cardiovascular disease and cancer.

e13716 Background: Adults living with both cardiovascular disease (CVD) and cancer represent a high-risk and understudied population with complex health needs. Often referred to as the cardio-oncology population, these individuals experience overlapping cardiovascular and cancer-related challenges. As digital health technologies increasingly shape how people access health information and engage with care, understanding health information seeking and digital health engagement in this population is critical. However, nationally representative evidence on technology use and health status among adults with co-occurring CVD and cancer remains limited. This study aimed to characterize patterns of health information seeking, digital health engagement, and health status in this population. Methods: This cross-sectional descriptive study used data from HINTS 7. The analytic sample included 419 adults who self-reported diagnoses of both CVD and cancer with complete data on key variables. Sociodemographic and clinical characteristics, health information-seeking behaviors, and digital health engagement were examined. Health status was assessed using self-rated general health and indicators of physical, functional, and mental health. Descriptive statistics summarized participant characteristics. Group differences by sociodemographic factors and health status were examined using chi-square tests, t-tests or ANOVA, as appropriate. All analyses accounted for the complex survey design and were conducted in R Studio. Results: Among 419 adults with co-occurring CVD and cancer, the mean age was 57.2 years (SD = 11.2), and 51.2% were female. Skin cancer was the most prevalent cancer type (21.5%). Most participants reported using the internet to seek health information. However, engagement with specific digital health tools, including telehealth services and electronic medical records, varied across the sample. Digital health engagement was lower among older adults and those with lower socioeconomic status. In addition, participants reporting poorer general health, physical or functional limitations, and mental health concerns demonstrated lower levels of digital health engagement compared with those reporting better health. Conclusions: This study provides a description of health information–seeking behaviors, digital health engagement, and health status among U.S. adults living with both CVD and cancer. In an understudied cardio-oncology population within the context of a rapidly evolving digital health landscape, these findings offer timely insights into current patterns of technology use and highlight sociodemographic and health-related differences that may inform future patient-centered digital health strategies.

Comparative effectiveness of radical surgery versus concurrent chemoradiotherapy in stage IB3, IIA2, or iiiCr cervical cancer: A prospective, multicenter, propensity score–matched cohort study.

e17503 Background: While concurrent chemoradiotherapy (CCRT) is the standard first-line treatment, radical surgery (RS) is frequently preferred in China, despite unclear comparative efficacy. The role of minimally invasive surgery also remains controversial and requires further validation. These persistent uncertainties underscore the need to advance research into LACC treatment strategies. Methods: We conducted a multicenter prospective cohort study at three tertiary teaching hospitals in Shanghai, including 246 patients with specific locally advanced cervical cancer (LACC; FIGO 2018 stages IB3, IIA2, or IIICr). We compared overall survival (OS), progression-free survival (PFS), adverse events (AEs), and two-year quality-adjusted life years (QALYs) between RS (n = 198) and definitive CCRT (n = 48), and further compared tumor-free laparoscopic RS (n = 119) with open RS (n = 79). Propensity score matching (PSM) was applied to reduce potential confounding. Subgroup analyses were conducted according to key clinical factors, and sensitivity analyses were performed to assess the robustness of the results. Results: After PSM, there were no significant differences in OS or PFS between the RS and the definitive CCRT groups (Two-year OS: 92% [86–97%] vs. 91% [82–100%]; Two-year PFS: 79% [72–87%] vs. 78% [66–91%]), nor between the tumor-free laparoscopic and the open RS groups (Two-year OS: 97% [93–100%] vs. 91% [84–98%]; Two-year PFS: 82% [74–92%] vs. 78% [69–89%]). Subgroup and sensitivity analyses yielded consistent findings. Two-year QALYs were comparable between the RS and the definitive CCRT groups (23.55 [22.54, 24.00] vs. 23.53 [22.60, 23.80] months; w = 3148, p = 0.074), but significantly higher in the tumor-free laparoscopic RS group than in the open RS group (24.00 [23.52, 24.00] vs. 23.52 [21.77, 24.00] months; w = 3060, p = 0.003). Conclusions: RS and definitive CCRT provided comparable survival outcomes and two-year QALYs in specific LACC patients (FIGO 2018 stages IB3, IIA2, or IIICr). Within the surgical cohort, tumor-free laparoscopic RS achieved similar survival outcomes as open RS but offered better two-year QoL benefits, supporting its role as a potential surgical option under strict oncologic principles. Clinical trial information: ChiCTR2000041315.

Update results of benmelstobart (BEN) combined with concurrent chemoradiotherapy (cCRT) versus cCRT alone as neoadjuvant therapy for esophageal squamous cell carcinoma (ESCC): A multicentre, randomised study.

e16112 Background: Standard neoadjuvant concurrent chemoradiotherapy (cCRT) for resectable ESCC yields only a 20-30% pathological complete response (pCR) rate. With immunotherapy has been approved for advanced ESCC, exploring its combination with cCRT in the neoadjuvant setting is imperative. Methods: This multicentre, randomised phase II trial planned to enroll 100 patients with resectable ESCC (T1-3N+M0/T3NanyM0). Patients were randomised 1:1 to benmelstobart (BEN) + cCRT or cCRT alone, stratified by cT stage (T1-2 vs T3). The BEN+cCRT group received BEN (1200mg, D1 and 22) plus cCRT (paclitaxel/carboplatin, 41.4 Gy/23 fraction of radiotherapy), while the cCRT group received cCRT alone. Surgery followed 6-8 weeks later. The primary endpoint was pCR rate in primary tumor site and lymph node. Secondary endpoints included MPR, ORR, DCR, R0 resection, 1-year DFS/OS rate, and safety. A preplanned radiation de-escalation to 36 Gy would be triggered if &gt; 18 of the first 30 BEN+cCRT patients achieved pCR in first stage. Results: From Oct 24, 2024, to Nov 20, 2025, 82 patients were randomised to BEN+cCRT (n = 42) or cCRT alone (n = 40). Four patients in BEN+cCRT group withdrew after randomization without treatment. In the full analysis set (FAS), 38 and 40 patients were analyzed, respectively. 73.1% of patients were ECOG PS 1. 16.7% of patients had primary tumor in upper esophagus. Thirty-seven and 40 patients completed neoadjuvant therapy, respectively. The ORR was 55.3% vs 60.0% in each group. Surgery rates were 73.7% (28/38) vs 90.0% (36/40). Of them, the primary endpoint pCR rates were 50.0% (14/28) vs 36.1% (13/36); MPR rates were 89.3% (25/28) vs 61.1% (22/36), respectively. Grade ≥3 TEAEs occurred in 73.7% vs 60.0% of patients, with hematologic toxicity being the most common. No grade ≥3 radiation esophagitis or grade 5 TEAEs were observed. Conclusions: Despite not meeting the prespecified endpoint of the first stage and without a radiotherapy dose reduction, BEN plus cCRT shows potential efficacy as neoadjuvant therapy in resectable ESCC, with encouraging pCR rate, MPR rate and a manageable safety profile. Clinical trial information: NCT06637163 . The pathological and surgical outcomes. Patients had surgery Patients had surgery FAS FAS BEN+cCRT (n=28) cCRT (n=36) BEN+cCRT (n=38) cCRT (n=40) pCR rate, n (%) 14 (50.0%) 13 (36.1%) 14 (36.8%) 13 (32.5%) pCR rate in primary tumor site, n (%) 17 (60.7%) 16 (44.4%) 17 (44.7%) 16 (40.0%) MPR rate, n (%) 25 (89.3%) 22 (61.1%) 25 (65.8%) 22 (55.0%) R0 resection, n (%) 28 (100%) 35 (97.2%) 28 (73.7%) 35 (87.5%) Tumor regression grade, n (%) 0 / 1 17 (60.7%) / 8 (28.6%) 16 (44.4%) / 5 (13.9%) 17 (44.7%) / 8 (21.1%) 16 (40.0%) / 5 (12.5%) 2 / 3 1 (3.6%) / 1 (3.6%) 8 (22.2%) / 6 (16.7%) 1 (2.6%) / 1 (2.6%) 8 (20.0%) / 6 (15.0%) Missing 1 (3.6%) 1（2.8%） 11 (28.9%) 5（12.5%）

Final results and preliminary correlative analysis of a phase I study of anetumab ravtansine in combination with checkpoint inhibitors and gemcitabine in mesothelin-positive advanced pancreatic adenocarcinoma (NCI10208).

4205 Background: Anetumab-ravtansine (AR) is an ADC composed of IgG1 targeting the protein mesothelin (MSLN) linked to DM4, a tubulin inhibitor ( Spiliopoulou, ASCO 2022 ). Here, we present the final analysis of a phase I study evaluating AR in combination with nivolumab, ipilimumab, or gemcitabine in patients (pts) with metastatic pancreatic adenocarcinoma (PDAC). Methods: Eligible pts had histologically confirmed MSLN-positive PDAC (≥5% expression by IHC), ECOG 0–1, and progression after ≥1 prior line of systemic therapy. The dose-escalation phase included: AR + nivolumab (ARM1), AR + nivolumab + ipilimumab (ARM2), and AR + gemcitabine + nivolumab (ARM3). The latter was chosen for dose-expansion. Two dose levels of AR: DL1 5.5 mg/kg and DL2 6.5 mg/kg (RP2D) were evaluated. Blood and tissue-based correlative analysis included paired tumor biopsies on C1D7 and C2D7 for comparison of immune cell shifts by multiplex immunofluorescence. Results: As of the final data cutoff on 15/11/2023, 46 pts were treated: ARM1 (n = 11), ARM2 (n = 13), ARM3 (n = 10), and dose expansion (n = 12). Median age was 66 years (40–83), the majority were males (52.2%) and had received prior gemcitabine (63%). The median number of prior treatment lines was 2 (1–5). Among 44 evaluable pts, 95.7% experienced some treatment emergent adverse events, with G1/2 and G≥3 occurring each at 47.8%. Dose limiting toxicities occurred in 6 pts (13%): 2 in ARM2DL2 (upper gastrointestinal hemorrhage and G3 thrombocytopenia), 2 in ARM3DL2 (G3 AST and G3 ALT elevation), and 1 in each of the dose expansion DL2 (G3 AST and G3 ALT elevation). Blurred vision occurred in 13%, peripheral neuropathy in 6.5%, pneumonitis in 4.3%, and keratitis in 2.2%, most of them being G1/2. No treatment-related deaths occurred. Among 41 evaluable pts, 1 (2.2%; ARM3DL2) had a complete response, 20 (43.5%) had stable, and 20 (43.5%) had disease progression. The median duration of treatment was 7.9 (1.9-32.9) weeks which was statistically longer in pts with stable disease than those with progressive disease as best response (16.4 vs 6.3 weeks, respectively; p &lt; 0.05). Twenty-seven pts were included in the multiplex immunofluorescence, and no statistically immune-cell shifts were detected between C1D7 and C2D7. Conclusions: AR had an acceptable safety profile in PDAC and the 6.5 mg/kg was identified as the R2PD. Evidence of clinical benefit was observed with some pts with prolonged disease stabilization and one complete response in a setting of limited therapeutical options. Correlative analysis to identify predictive biomarkers for treatment benefit is ongoing. Clinical trial information: NCT03816358 .