Body composition may influence outcomes in muscle-invasive bladder cancer (MIBC), but its prognostic role remains unclear. In particular, the impact of adipose tissue distribution and muscle quality beyond BMI has been insufficiently studied. This study aimed to evaluate whether adipose tissue distribution and myosteatosis assessed by AI-based CT analysis are associated with OS in patients with MIBC treated with neoadjuvant chemotherapy followed by radical cystectomy. In this retrospective, bicentric study, we analyzed data from 87 patients with MIBC treated with neoadjuvant chemotherapy (NAC) followed by radical cystectomy. Artificial intelligence (AI)–based analysis was applied to CT scans obtained before chemotherapy (BC) and before surgery (BS), focusing on the L3 vertebral level. We assessed the association between body composition and OS, and secondarily progression-free survival (PFS). Evaluated parameters included myosteatosis (fat infiltration of skeletal muscle), subcutaneous fat index (SFI), visceral fat index (VFI), and the visceral-to-subcutaneous fat ratio (VSR). Median follow-up was 24.6 months. A high SFI measured before surgery was significantly associated with improved OS (HR 0.41; 95

Background Patients with advanced pancreatic ductal adenocarcinoma (aPDAC) often experience general health decline at diagnosis due to a high-symptom burden. The optimal management of symptoms and/or poor performance status (PS) in these patients remains an unmet medical need. Patients and Methods In this multicenter study, patients with PS≥2 and pathologically confirmed or imaging-suspected aPDAC were included at first oncology visit in a personalized 14-day emergency integrative supportive care program (14-EISCP) to manage pain, nutrition, diagnostics, and stenting procedures. The primary endpoint was the 14-EISCP success in feasibility of planned procedures and clinical benefit defined as post-EISCP PS≤1, ≥5 points improvement in fatigue, pain, global health-related quality of life (HRQoL) scores (EORTC QLQ-C15-PAL), or chemotherapy initiation within 30 days. Results A total of 106 patients were included; 93 evaluable patients considered for primary endpoint analysis (median age: 76 years [68-80], PS3: 20.9%, metastases: 61.3%). The median overall survival was 4.1 months (IC95% 2.6-5.6). The 14-EISCP was successful in 59.1% (n=55) of patients, meeting the primary objective (clinically relevant). The 14-EISCP feasibility was achieved in 70.9% of cases. Post-EISCP clinical benefit was observed in 79.6% of patients, with PS improvement to 0/1 in 13.2%, HRQoL improvement in 23.9%, and chemotherapy initiation ≤30 days in 73.1%. Among evaluable patients, 17.2% received mFOLFIRINOX or gemcitabine-nab-paclitaxel, 35.4% received FOLFOX, 25.3% had gemcitabine or 5-fluorouracil alone, and 22.2% received best supportive care. In patients with PS2 at baseline, the administration of doublet/triplet chemotherapy was associated with improved overall survival compared to single-agent. Discussion These results offer a promising framework for improving outcomes in aPDAC patients, bridging the gap between symptom management and systemic therapy administration. Conclusions In patients with PS≥2 and aPDAC, the personalized 14-EISCP was feasible and lead to meaningful clinical benefit, allowing doublet or triplet chemotherapy in half the patients.

Purpose To develop and validate an automated CT body-composition pipeline for sarcopenia assessment in borderline resectable pancreatic cancer (BRPC), combining L3 selection with hybrid Swin Transformer–CNN segmentation. Methods This retrospective multicenter study included 110 patients with BRPC treated between 2015 and 2023. A CNN–RNN model performed automated L3 slice selection. A hybrid Swin Transformer–CNN network with a Hybrid Attention Feature Fusion Module segmented skeletal muscle, subcutaneous adipose tissue, and visceral adipose tissue. Internal validation used 66 L3 slices. Independent expert validation used 111 L3 slices annotated for skeletal muscle by two blinded senior radiologists, enabling comparison with inter-observer agreement and a strict consensus reference. Automated skeletal muscle index (SMI) classified sarcopenia, and survival was analyzed using Kaplan–Meier curves and log-rank tests. Results The slice-selection model achieved 96.9 % overall accuracy and 96.7 % accuracy on a heterogeneous external test set. On internal validation, Dice scores were 0.97 for skeletal muscle, 0.97 for subcutaneous adipose tissue, and 0.91 for visceral adipose tissue. Against the strict two-radiologist skeletal muscle consensus, the model achieved a Dice score of 0.94, approaching the inter-observer Dice score of 0.975. Automated SMI classified 10/96 patients as sarcopenic. Sarcopenia was associated with shorter overall survival (16 vs. 26 months, p = 0.02), whereas progression-free survival was not significant (12 vs. 16 months, p = 0.14). Conclusion This automated hybrid Swin Transformer–CNN pipeline achieved high segmentation performance and enabled sarcopenia-based overall survival stratification in BRPC. External validation and formal ablation studies are warranted.

Antiangiogenic therapies have been extensively investigated in advanced/metastatic gastric cancers, but also in neoadjuvant settings. The anti-Vascular Endothelial Growth Factor Receptor 2 (VEGFR2) monoclonal antibody ramucirumab was the first antiangiogenic agent approved for HER2-negative metastatic gastric adenocarcinomas and remains a standard second-line treatment either alone or in combination with paclitaxel. Other VEGFR-targeting agents, such as the tyrosine kinase inhibitors (TKI) regorafenib and apatinib, have failed to demonstrate any survival benefit in the first-line settings, while providing modest improvements in pretreated patients, even when combined with Immune Checkpoint Inhibitors (ICI). Despite showing no significant benefit in Caucasian patients, apatinib has been approved in China for pretreated patients with advanced/metastatic gastric cancer. Dose-limiting toxicities, and the lack of robust predictive biomarkers for patients' stratification may both contribute to the limited efficacy of these multi-target tyrosine kinase inhibitors in gastric cancers. Several ongoing clinical trials mostly conducted in China suggest that new generation of antiangiogenic agents, particularly bispecific antibodies targeting both VEGF and Programmed Cell Death 1 (PD-1) or its ligand PD-L1, may offer greater efficacy with reduced toxicity. However, these promising preliminary data await mature overall survival results as well as clinical validation in the global population. Developing more effective drugs is closely linked to identifying reliable predictive biomarkers, which are crucial for guiding patients' selection, monitoring treatment response and optimizing therapeutic combinations and sequencing. Although several biomarker candidates have been explored, reliable predictors are still awaited. This review summarizes current evidence and explores the future of antiangiogenic agents in gastric cancers.

Background: Screening for clinical trials is challenging for clinicians due to its time-consuming and repetitive nature. The rise of artificial intelligence (AI) offers an opportunity to improve screening productivity and reproducibility. Pancreatic cancer is characterized by increasing incidence, poor survival outcomes, and an urgent need for improved management strategies. Objective: This study aimed to assess the performance of AI in evaluating clinical trial inclusion and exclusion criteria, compared to a double-blind human gold standard, using a retrospective cohort. Methods: In the PANCR-AI (Pancreatic Cancer Retrospective Screening with Artificial Intelligence) pilot study, we retrospectively reviewed cases from our institutional database of patients with advanced pancreatic cancer presented at tumor board meetings between January 2018 and December 2023. Each patient was screened for clinical trials open for inclusion at the time of the multidisciplinary meeting. Manual screening of eligibility criteria for each patient-trial pair was performed by 2 blinded oncologists to determine potential eligibility (gold standard), with a third oncologist resolving discrepancies. Potential eligibility was also assessed using 3 large language models (ie, GPT-4.5, Claude 3.7 Sonnet, and Mistral-7B-Instruct v0.3). Their performance was compared to the human gold standard using standard evaluation metrics (eg, sensitivity, specificity, precision, recall, and F1-score). Correlations between the risk of failure and the number of words and characters in the criteria were analyzed. The time required to complete the screening was recorded for both human and AI assessments. The number of trials open for enrollment at the time of the tumor board meeting was also recorded as a variable for analysis. Results: Across 341 patient-trial pairs, the AI models demonstrated high sensitivity, ranging from 83.3% to 92.2%. Analysis of the criteria showed a correlation between the risk of failure and the number of words and the number of characters in the criteria. Overall screening time for manual assessment was significantly longer for the human gold standard (44.70 hours) assessment than for AI (2.53-3.15 hours). Patients were more likely to have been included in a clinical trial if the number of trials open for enrollment was higher at the time of the tumor board meeting (P=.02). Conclusions: Our study highlights the promising performance of AI in clinical trial screening. Future work should explore integration with structured clinical data, such as laboratory values or radiological findings, to improve multimodal comprehension. Expanding the evaluation to a broader range of tumor types and multicenter datasets would improve generalizability. Finally, real-time prospective validation and workflow integration with electronic health records will be critical to assess the feasibility and clinical impact of large language model-assisted screening in daily oncology practice. Addressing these challenges will be essential to move from proof of concept to scalable clinical implementation.

Excessive cortisol secretion is responsible for metabolic complications, increasing morbidity and mortality. Normalizing cortisol levels with surgery or medical treatments are the most effective ways to limit these complications, but few studies have compared these two strategies specifically on metabolic complications. This observational, retrospective, monocentric study included 62 patients with confirmed endogenous ACTH-independent hypercortisolism followed in our department between January 2019 and January 2024. Patients were included in three groups: surgery (n = 42), medication (n = 13), and observation (n = 7). Metabolic complications were assessed at baseline, 6 months and 12 months. We compared the evolution of complications depending on the therapeutic strategy and according to the underlying etiology of hypercortisolism. After 6 months, patients in both surgery and medication group showed improvements in cortisol levels, weight, blood pressure, lipid profile, diabetes, and liver parameters. Weight loss was higher in the medication group (-1.61 VS + 0,25 kg/m² in surgery group) while there was no difference for the other parameters. This difference was persistentat 12 months. Patients with primary bilateral macronodular adrenocortical hyperplasia (PBMAH) who received medication showed a higher reduction in BMI (-1,98 VS + 0,68 kg/m²), systolic and diastolic blood pressure (-11,6 VS + 3 and − 4,5 VS + 5 mmHg respectively) than operated patients. No significant differences were observed for other etiologies. Our study suggests that medical treatment is more effective than surgery to improve weight in ACTH-independent hypercortisolism, especially in patients with PBMAH. Treatment modality does not appear to have any impact on other short-term metabolic complications.

PURPOSE The choice of adjuvant chemotherapy in pancreatic ductal adenocarcinoma (PDAC) is mainly guided by patients' general condition. We hypothesized that tumor morphology may predict differential treatment benefit and tested whether deep learning applied to histology images could derive a biomarker of relative benefit from gemcitabine (GEM) versus modified FOLFIRINOX (mFOLFIRINOX) in resected PDAC. PATIENTS AND METHODS Standard whole-slide images from a retrospective multicentric series of 231 patients who underwent curative-intent pancreatectomy and received adjuvant mFOLFIRINOX (n = 54) or GEM (n = 177) were used to train regimen-specific histology models on disease-free survival (DFS), which were then combined into PANCprAId, a biomarker estimating personalized relative benefit from adjuvant GEM versus mFOLFIRINOX. External validation was performed in the randomized PRODIGE-24/CCTG PA6 trial (n = 313). RESULTS In PRODIGE-24/CCTG PA6, the treatment-specific histology scores used to construct PANCprAId stratified outcomes among patients treated with GEM (hazard ratio [HR], 1.69 [95% CI, 1.04 to 2.73]; P = .03) and mFOLFIRINOX (HR, 2.02 [95% CI, 1.4 to 3.0]; P < .001). When combined into PANCprAId, the biomarker identified subgroups with differential relative benefit from adjuvant GEM versus mFOLFIRINOX, with significant treatment interactions for DFS (interaction P = .003) and cancer-specific survival (interaction P = .001). Predicted sensitivity to each regimen was associated with distinct epithelial and stromal features. CONCLUSION Histology-based deep learning can derive a predictive biomarker of relative benefit from adjuvant GEM versus mFOLFIRINOX in resected PDAC.

Background: Sarcopenia is a recognized adverse prognostic factor in many cancers and can be reliably assessed using computed tomography (CT) scans. Its prognostic value in bladder cancer patients undergoing neoadjuvant chemotherapy remains underexplored. This study aimed to assess sarcopenia's impact on survival and compare different measurement thresholds. Methods: We conducted a retrospective multicenter study including patients with invasive urothelial carcinoma treated with neoadjuvant chemotherapy followed by cystectomy between 2015 and 2021. Sarcopenia was assessed by measuring the Skeletal Muscle Index on CT scans before chemotherapy (BC) and prior to surgery (BS). The primary endpoint was overall survival. Secondary endpoints included progression-free survival (PFS), pathological complete response (pCR), and treatment-related complications. Results: Seventy-four patients were included, the majority receiving the MVAC regimen (71.7%). Forty percent of patients achieved a pCR, 35% experienced disease recurrence, and the median PFS was 25 months. Sarcopenia was observed in 27% of patients BC and in 39% BS. Sarcopenia was associated with an increased risk of all-cause mortality: BC according to the definition by Martin et al. (HR 3.38; 95% CI [1.25-9.12]; p = 0.016) and Fearon et al. (HR 4.03; 95% CI [1.13-14.3]; p = 0.031); and BS according to Martin et al. (HR 3.7; 95% CI [1.12-12.2]; p = 0.032) and Fearon et al. (HR 6.08; 95% CI [1.48-24.9]; p = 0.012). Sarcopenia was an independent risk factor of shorter PFS. Conclusions: Sarcopenia represent an independent and reproducible prognostic factor for mortality in patients with bladder cancer. The study is the first study to compare threshold values at different time points.

Objective:To investigate the correlation between positive resection margins and outcomes in patients with pancreatic ductal adenocarcinoma who underwent surgery and adjuvant chemotherapy according to the pivotal trial PRODIGE 24-CCTG PA-6. Background:The primary focus is on elucidating the prognostic significance of specific resection margins, including those associated with the superior-mesenteric vein, medial, and posterior pancreas. Methods:The analysis involved 400 patients across multiple centers in France and Canada. Surgical resection and subsequent adjuvant chemotherapy were core interventions. This study assessed the prognostic impact of resection margins, highlighting the significance of standardized pathology assessments. In addition, the influence of chemotherapy regimen choice, comparing gemcitabine to mFOLFIRINOX, on the implications of positive resection margins was examined. Results:Only 3 margins, superior-mesenteric vein [hazard ratio (HR) = 1.48 (95% CI: 1.11; 1.96); P < 0.001], medial [HR = 1.92 (95% CI: 1.36; 2.73); P < 0.001] and posterior [HR = 1.65 (95% CI: 1.21; 2.24); P = 0.002], had a significant prognostic impact on disease-free survival and were sufficient compared with the 7 recommended margins (Kappa = 0.90; 95% CI: 0.87; 0.94). R1 status was a significant independent prognostic factor for poorer survival in gemcitabine-treated patients [HR = 1.97 (95% CI: 1.23; 3.16); P = 0.005] but lost its significance with mFOLFIRINOX [HR = 1.46 (95% CI: 0.91; 2.35); P = 0.114]. Conclusions:All efforts should be made to evaluate the 3 margins of the highest prognostic value, with the others being secondary. A key finding of this study is the likely effect of mFOLFIRINOX on local invasion in operated patients, which seems to correct the impairment related to margin involvement, probably explaining the improvements in disease-free survival and overall survival.

PURPOSE:Modified fluorouracil, leucovorin, irinotecan, and oxaliplatin (mFOLFIRINOX/mFFX) is the standard adjuvant chemotherapy for resected pancreatic ductal adenocarcinoma (PDAC), offering survival benefits over gemcitabine (GEM). However, the contribution of molecular biomarkers to treatment selection remains unclear. Here, we characterize the molecular landscape of tumors from the PRODIGE-24/CCTG PA6 trial and assess the clinical impact of genomic alterations and molecular subtypes. PATIENTS AND METHODS:Tumor DNA sequencing was successfully performed in 317/350 tumors (168 mFFX; 149 GEM), complemented by transcriptomic subtyping using the PurIST classifier. Mutational status of four key PDAC driver genes and 24 homologous recombination repair (HRR)-associated genes was analyzed, alongside single-base substitution (SBS) mutational signatures. Primary and secondary end points were disease-free survival (DFS) and cancer-specific survival (CSS), respectively. RESULTS:In the mFFX group, the PurIST subtype was prognostic, with classical tumors showing superior DFS compared with basal-like tumors (stratified hazard ratio [sHR], 0.48 [95% CI, 0.31 to 0.77]). Among KRAS-mutated patients, mFFX significantly improved DFS compared with GEM (sHR, 0.60 [95% CI, 0.45 to 0.79]; P < .001), while no benefit was observed in KRAS wild-type tumors (interaction test, Pint. = 0.010). HRR and BRCA status were not predictive (Pint. = .568 and Pint. = .785, respectively). The benefit of mFFX was consistent across SBS-positive and SBS-negative subgroups. CONCLUSION:Overall, these results do not support a change in current adjuvant treatment strategies. mFFX remains the standard adjuvant regimen in PDAC, and the observed lack of benefit in KRAS wild-type tumors should be considered hypothesis-generating and warrants further investigation.

e16380 Background: With a 5-year overall survival (OS) rate <5%, PDAC is a major cause of cancer-related mortality. OPTIMIZE-1 is an open-label, single-arm, multicenter phase 1b/2 study to evaluate efficacy and safety of mitazalimab, a human CD40 agonistic IgG1 antibody, in combination with mFFX in untreated patients with mPDAC. The study met its primary endpoint with promising clinical efficacy vs. historical controls resulting in an overall response rate (ORR) of 54.4 % (unconfirmed; 42.1% confirmed) (Van Laethem 2024). We report the final efficacy analysis for patients treated with 450 and 900 µg/kg mitazalimab. Methods: Patients received mitazalimab on day 1 (priming dose), followed by a 2-week regimen starting with mFFX on day 8 and mitazalimab on day 10. The primary endpoint was ORR compared to 30% ORR for FFX alone. Secondary and exploratory endpoints include Duration of Response (DoR), Progression Free Survival (PFS), OS, safety, PK and PD biomarker assessments. Results: Between 2021 and 2025 94 patients with mPDAC were treated with mFFX + mitazalimab (29 at 450 µg/kg and 65 at 900 µg/kg). 22 patients at 450 µg/kg and 57 at 900 µg/kg received ≥2 treatment cycles and were efficacy evaluable. Efficacy outcomes for both dose levels are summarized in Table 1. The 900 µg/kg dose presented higher ORR, DoR, mPFS and mOS and has been selected for Phase 3 development. The primary efficacy analysis comprised 57 evaluable patients treated with 900 µg/kg mitazalimab + mFFX. Median follow up was 36 months and median exposure to treatment was 7 months. Eighteen patients remained treatment for more than 12 months, including seven who continued beyond 24 months. One patient remains on treatment. ORR was 54.4% (42.1% confirmed) and 22 patients achieved stable disease, for a disease control rate of 78.9%. Three patients achieved complete responses (CR) in target lesions, including one with CR in target and non-target lesions. Median DoR was 12.6 months, mPFS was 7.7 months and mOS was 14.9 months (12, 18, 24 and 30-mo OS rates of 58%, 37%, 26% and 21% respectively). Conclusions: Mitazalimab (900 µg/kg) in combination with mFFX continues to demonstrate clinically meaningful survival benefits compared with historical controls. The robust duration of response and encouraging long-term survival—six patients surviving >36 months—support continued development of mitazalimab in a confirmatory Phase 3 study. Clinical trial information: NCT04888312 . 450 µg/kg(N=22) 900 µg/kg(N=57) Median follow up (95% CI) 13.1 (12.1 - 13.9) 36.2 (30.9 - 36.7) ORR n % (90% CI) 5 (22.7) 24 (42.1) DoR (95% CI) NE (3.7 - NE) 12.6 (7.5 - 22.0) mPFS (95% CI) 5.3 (2.0 - 9.2) 7.8 (5.8 - 11.5) mOS (95% CI) 9.7 (5.9 - NE) 14.9 (10.0 - 17.3) 12-month OS, % (95% CI) 42.9 (21.9 - 62.3) 57.8 (43.9 - 69.4) 18-month OS, % (95% CI) 32.1 (11.1 – 55.7) 37.3 (24.8 - 49.9) 24-month OS, % (95% CI) - 26.1 (15.4 - 38.2) 30-month OS, % (95% CI) - 20.5 (11.0 - 32.1)

BACKGROUND:A better prognosis is suggested for lung-only metastases patients with pancreatic ductal adenocarcinoma (PDAC), yet biological/clinical underpinnings of organotropism in PDAC remain unclear. Study objective was to compare PDAC patients depending on their metastatic site with a special focus on "lung-only" metastases patients. METHODS:A retrospective analysis included all patients with metastatic PDAC between 2010 and 2022 in an academic-center. Lung-only patients were defined as patients with only lung metastases at diagnosis of metastases. RESULTS:Among 1012 patients, 109 (11 %) presented lung-only metastases, 506 patients (50 %) liver-only, 94 (9 %) peritoneal-only and 303 (30 %) other or multiple sites. Compared with others, lung-only patients were more frequently female (63 % vs. 46 %), older at metastatic diagnosis (median 66 vs. 63 years, p = 0.01), and less likely to have synchronous metastases (42 % vs. 69 %, p < 0.001). ctDNA detection was lower in the lung-only group with less KRAS mutations and TP53 mutations detected with liquid biopsy (but no difference was observed using tumor tissue). Median OS was higher in the lung-only group with 28.7 months (95 %CI [23.3-38.6]) vs 13.5 months (95 %CI [12.4-14.6]) for liver-only group, 11.5 months (95 %CI [9.6-16.9]) for peritoneal-only group and 11.3 months (95 %CI [10.0-13.8]) for other patients (p < 0.0001). Among lung-only patients, local treatments (n = 15) had a positive prognostic impact. CONCLUSIONS:Patients with lung-only metastases had a better OS than others, were more often women, and harbored less KRAS mutations. Our results argue in favor of PDAC with specific characteristics, especially a better prognosis, possibly further enhanced by the possibility to perform local treatments, and less detection of ctDNA.

Sarcopenia, characterized by a loss of skeletal muscle mass and function, is a poor prognosis risk factor in various cancers. Diagnosis typically involves quantifying skeletal muscle area at the L3 vertebral level (SMA) using CT imaging, however a universally accepted definition of sarcopenia does not exist. In a retrospective, multicenter study, we analyzed data from 87 muscle-invasive bladder cancer patients who received neoadjuvant chemotherapy followed by radical cystectomy. Artificial intelligence (AI) was used to evaluate CT scans obtained before chemotherapy (BC) and before surgery (BS), focusing on the L3 vertebral level. Sarcopenia was defined using four distinct criteria from the existing literature. The primary objective of this study was to assess the reliability of AI-based versus manual measurements of sarcopenia while secondary endpoints included, overall survival (OS), progression-free survival (PFS), and the impact of undernutrition and neutrophil-to-lymphocyte ratio (NLR) on OS. 87 patients were included in the final analysis. AI-based SMA measurements were highly correlated with manual measurements (r = 0.95; p < 0.001). Sarcopenia BC and BS, as defined by the Pardo criteria, was significantly associated with poorer OS (Prado BC: HR 2.26, 95

BACKGROUND:In Europe, pembrolizumab with or without chemotherapy is the recommended first-line treatment for recurrent or metastatic head and neck squamous cell carcinoma (R/M HNSCC), with a combined positive score (CPS) ≥ 1. In France, the TPExtreme (TPEx) regimen is preferred for CPS < 1. These regimens were studied in selected populations, which may not reflect real-world patients. METHODS:We reviewed all R/M HNSCC cases treated with first-line regimens between January 2021 and December 2023 in Nancy and Lille. Data on patient history, treatments, survival, response, and safety were collected. PFS and OS were analyzed using the Cox multivariable regression model, adjusting for the covariates age, Eastern Cooperative Oncology Group (ECOG) performance status, comorbidities, and nutritional status. RESULTS:The analysis included 290 patients; 19% received pembrolizumab alone, 28% received pembrolizumab with chemotherapy, 19% received TPEx, and 20% received adapted regimens. PFS and OS differed significantly between groups. Median PFS and OS were respectively 2.9 and 9.4 months for pembrolizumab, 6 and 15.5 months for pembrolizumab-chemotherapy, 5.9 and 13.7 months for TPEx, and 4.3 and 10 months for adapted regimens. Pembrolizumab alone is the safest regimen. CONCLUSION:This retrospective study reflects real-world first-line therapy for R/M HNSCC in two French cancer institutes. Pembrolizumab combined with chemotherapy is the preferred treatment option.

4009 Background: OSE2101 is an off the shelf vaccine made of 10 synthetic HLA-A2-restricted peptides targeting 5 tumor associated antigens. This multicenter, randomized, non-comparative, phase II study assessed FOLFIRI ± OSE2101 maintenance in aPDAC Pts without progression after 8 cycles of FFX. Methods: Eligible aPDAC Pts were randomized to FOLFIRI (Arm A) or FOLFIRI + OSE2101 (Arm B: subcutaneous injection on D1, D15, Q4W/6 doses then Q8W to M12 then Q12W up to M24). Stratification factors: tumor stage (locally advanced vs metastatic), best response to FFX (partial or complete response [CR, PR] vs stable disease [SD]), and center. Primary endpoint: overall survival (OS) rate at M12 in evaluable Pts (M12-OS; Fleming 2-stage design, H0: 25%; H1: 50%, 1-sided alpha: 2.5%, power: 90%); secondary endpoints: progression-free survival (PFS; RECIST v1.1), best response, duration of disease control (DDC), and safety. Results: 107 Pts (ITT) were randomized (53/Arm A, 54/Arm B) between 04/2021 and 05/2023. Median age 64 years (range:37-81), 53% men, 69% had metastases, 36%/64% had PR/SD to prior FFX. No evidence of imbalance in Pt characteristics was observed between arms. Median number of OSE2101 injections was 7.5 (1-14). Median treatment duration of FOLFIRI was 5.4 months in both arms. At data cut-off (Dec 9, 2024), median follow-up was 21.4 months with 101 evaluable Pts for M12-OS (49/Arm A, 52/Arm B; 4 consent withdrawals, 1 Pt’s decision, 1 treatment interruption >4 weeks). Number of death events (n/%) was 19/35.8% in Arm A and 18/33.3% in Arm B. M12-OS (95%CI) was 61% (46.2%-74.8%) in Arm A and 65% (50.9%-78.0%) in Arm B. Median (95%CI) OS and PFS (ITT) were 17.3 months (10.6–23.2) and 8.2 months (5.3–11.6) in Arm A, and 15.5 months (12.4–19.3) and 7.8 months (5.4–10.6) in Arm B. Other secondary endpoints are described in Table. Among 33 Pts with SD to prior FFX in Arm B, 6 (18%) had CR/PR (1/5) when adding OSE2101 to FOLFIRI vs 5 (no CR) among 35 Pts in Arm A. In the safety population, 7 SAEs/6 Pts (12%) in Arm A and 22 SAEs/14 Pts (26%) in Arm B were reported. No unexpected SAEs were observed with OSE2101 except 1 inappropriate administration, and no evidence of increased toxicity of FOLFIRI with OSE2101. Conclusions: TEDOPAM met its primary objective with minimal toxicity and positive outcomes of adding OSE2101 cancer vaccine to maintenance FOLFIRI, albeit mitigated by unexpectedly favorable OS in the control arm. Two complete responses were observed when adding OSE2101. Further follow-up is ongoing and translational analysis planned. Clinical trial information: NCT03806309 . ITT Arm AN=53 Arm BN=54 Best response, n (%) CR 0 (0.0) 2 (3.7) PR 12 (22.6) 10 (18.5) SD 28 (52.8) 34 (63.0) Progressive disease (PD) 8 (15.1) 8 (14.8) Missing 5 (9.5) 0 (0.0) DC rate, n (%) 40 (75.5) 46 (85.2) DDC (95% Cl) 8.8 (6.2-12.9) 9.8 (6.8-14.8)

Response determinants to immunotherapy in metastatic pancreatic ductal adenocarcinoma (mPDAC) remain unclear, limiting treatment advancements. We report a single-arm phase 1b/2 study (OPTIMIZE-1) evaluating the safety and efficacy of the cluster of differentiation 40 (CD40) agonist mitazalimab combined with modified FOLFIRINOX (mFOLFIRINOX), in chemotherapy-naive patients with mPDAC. Patients receive an initial dose of mitazalimab one week before starting biweekly cycles of mFOLFIRINOX plus mitazalimab. The study meets its pre-specified primary endpoint, achieving a confirmed objective response rate (ORR) of 42.1%. Median duration of response, progression-free survival, and overall survival was 12.6 months, 7.7 months, and 14.9 months, respectively. Multi-omic analyses of tumor and blood specimens identify a baseline tumor-intrinsic gene signature related to fibrosis associated with improved survival. Additionally, mitazalimab-induced increases in activated circulating myeloid, B cell, and T cell frequencies correlate with better outcomes. These results may inform future patient stratification strategies supporting a planned randomized confirmatory trial of mitazalimab with mFOLFIRINOX in mPDAC. This study was registered at ClinicalTrials.gov (NCT04888312).

Radiation therapy (RT) is a mainstay of treatment for a myriad of cancers; however, it remains a controversial option in the management of patients with pancreatic cancer. The prognosis for this disease remains one of the poorest, despite recent advances in chemotherapy, which still has limited efficacy and suffers from multiple forms of resistance. The application of RT in patients with pancreatic cancer remains largely institution and provider dependent. Despite advances in RT where higher doses can be delivered while sparing adjacent normal organs, local control remains a problem, highlighting the necessity for improvements in the current RT approach. Emerging strategies are currently being developed with the aim of improving the effects of RT using “radiosensitization” mechanisms. The objective of radiosensitization is to either enhance DNA damage induced by RT or to prevent its repair or to impair the RT-resistance-associated components of the tumor. The process of radiosensitization can be achieved through the use of conventional chemotherapy agents or by novel molecules that inhibit DNA damage response effectors, as well as cell cycle checkpoints. Additionally, nanoparticles with a high atomic number have the potential to act as radiosensitizers by enhancing the effects of RT specifically in tumor cells. Another avenue of radiosensitization entails the combination of immunotherapy with immune checkpoint inhibitors to increase the immunomodulatory impact of RT. The radiosensitivity of pancreatic ductal adenocarcinoma may also be enhanced by targeting components of the tumor microenvironment or metabolic characteristics associated with resistance to RT. This review aims to provide a comprehensive overview of cutting-edge radiosensitization strategies, from their initial preclinical studies to their current status in clinical trials.