Esophageal squamous cell carcinoma (ESCC) has limited treatment options post-immune checkpoint inhibitor (ICI) resistance. We developed IPM514, a universal multi-epitope mRNA lipid nanoparticle (LNP) vaccine targeting tumor-associated antigens identified via transcriptomic analysis of TCGA/GTEx datasets and validated in 132 ESCC patients. IPM514 contains 15 fragments from 9 antigens, covering most patients and over half of HLA subtypes. Peripheral blood mononuclear cells (PBMCs) from healthy donors and ESCC patients stimulated with IPM514 effectively expanded specific T cells that exhibited significant cytotoxic activity against ESCC and other squamous cell carcinomas with similar antigen profiles. In HLA-transgenic mouse models, IPM514 suppressed tumor growth, extended survival, and provided durable protection. Importantly, combination therapy with PD-1 blockade augmented antitumor efficacy by promoting immune cell infiltration, upregulating antigen presentation pathways, and reprogramming the tumor microenvironment toward an anti-tumorigenic state. These results demonstrate IPM514 represents a promising novel mRNA vaccine strategy for improving ESCC immunotherapy.

BACKGROUND:There is an unmet need for additional and more efficacious therapies for patients with unresectable metastatic oesophageal cancer. We aimed to evaluate the efficacy and safety of adding tiragolumab and atezolizumab to chemotherapy as first-line treatment for unresectable or metastatic oesophageal squamous cell carcinoma. METHODS:The SKYSCRAPER-08 randomised, double-blind, placebo-controlled, phase 3 trial was done at 67 centres in mainland China, South Korea, Thailand, Taiwan, and Hong Kong and enrolled adult patients (aged ≥18 years) with treatment-naive, unresectable locally advanced, unresectable recurrent, or metastatic oesophageal squamous cell carcinoma, with an Eastern Cooperative Oncology Group performance status of 0-1. Patients were randomly assigned (1:1) to receive tiragolumab (600 mg) plus atezolizumab (1200 mg) and chemotherapy (paclitaxel [175 mg/m2] and cisplatin [60-80 mg/m2]) or placebo and chemotherapy through intravenous infusion for six 21-day cycles. The primary outcomes were independent review facility-assessed progression-free survival and overall survival in the intention-to-treat population (defined as all randomly assigned patients, regardless of whether they received any study treatment). This study was registered with ClinicalTrials.gov, NCT04540211, and is ongoing. FINDINGS:Between Oct 30, 2020, and Nov 30, 2021, 461 patients were assigned to receive tiragolumab plus atezolizumab and chemotherapy (n=229) or placebo and chemotherapy (n=232); 406 (88%) were male and 55 (12%) female, and all patients were Asian. Median survival follow-up was 12·6 months (IQR 6·8-18·0). Median independent review facility-assessed progression-free survival (cutoff June 15, 2022) in the tiragolumab plus atezolizumab and chemotherapy group was 6·2 months (95% CI 5·7-7·2) versus 5·4 months (95% CI 4·4-5·5) in the placebo and chemotherapy group (HR 0·56, 95% CI 0·45-0·70; p<0·0001). Median overall survival (cutoff Feb 13, 2023) was 15·7 months (95% CI 13·3-20·4) and 11·1 months (95% CI 9·6-13·6; HR 0·70, 95% CI 0·55-0·88; p=0·0024). The most common grade 3-4 adverse events in the tiragolumab plus atezolizumab and chemotherapy group versus the placebo and chemotherapy group were white blood cell count decrease (46 [20%] of 228 vs 35 [15%] of 227), neutrophil count decrease (78 [34%] vs 78 [34%]), and anaemia (19 [8%] vs 24 [11%]). Serious adverse events occurred in 94 (41%) of 228 patients in the tiragolumab plus atezolizumab and chemotherapy group and 89 (39%) of 227 in the placebo and chemotherapy group; the most common serious adverse event was pneumonia (17 [7%] of 228 and 13 [6%] of 227). Treatment-related deaths occurred in six patients (3%) in the tiragolumab plus atezolizumab and chemotherapy group (immune-mediated lung disease, pneumonitis, cardiac arrest, gastrointestinal haemorrhage, hepatic failure, and bacterial pneumonia) and two (1%) in the placebo and chemotherapy group (gastrointestinal infection and death of unknown cause). No new safety signals were identified. INTERPRETATION:Independent review facility-assessed progression-free survival and overall survival were significantly better in the tiragolumab plus atezolizumab and chemotherapy group compared with chemotherapy alone for unresectable locally advanced, unresectable recurrent, or metastatic oesophageal squamous cell carcinoma. These data support the rationale for exploring dual checkpoint inhibition added to chemotherapy for this group of patients with a high unmet need. FUNDING:F Hoffmann-La Roche-Genentech.

Photodynamic therapy (PDT) is a localized treatment for esophageal stenosis and dysphagia in advanced cancer. This study evaluated the efficacy and safety of Cosiporfin sodium (DVDMS)-mediated PDT for dysphagia in advanced esophageal cancer. In this Phase II trial, patients with advanced esophageal cancer and Grade ≥ 2 dysphagia, who were unsuitable for or declined curative therapies, received 0.2 mg/kg DVDMS followed by PDT (wavelength: 630 nm) at varying regimens: 102 J/cm (24 h post-injection), 200 J/cm (24 h), and 150 J/cm (18 h). Safety was the primary endpoint. The study enrolled 20 patients in the 102 J/cm 24 h group, 6 in the 200 J/cm 24 h group, and 4 in the 150 J/cm 18 h group. Two patients experienced dose-limiting toxicities: One upper abdominal pain (16.7%) in the 200 J/cm 24 h group and one non-cardiac chest pain (25.0%) in the 150 J/cm 18 h group. Common adverse events included non-cardiac chest pain (10.0%) related to DVDMS and non-cardiac chest pain (20.0%) and anemia (20.0%) related to PDT. The photosensitivity test showed that by day 4, 66.7% of patients tested negative, improving to 86.7% by day 7, and all patients were negative by day 28. The esophageal overall response rate was 40.0% on day 28. The median duration of esophageal response and median OS for all patients were 4.86 months (95% CI: 1.51-5.32) and 9.51 months (95% CI: 5.45-NE), respectively. DVDMS-mediated PDT demonstrates acceptable safety and sustained efficacy in improving esophageal stenosis and dysphagia in advanced esophageal cancer. Trial Registration: chictr.org.cn ChiCTR2000032829.

Supplementary Table 1 Final Product Release Criteria for UTAA06 Supplementary Table 2 Representativeness of Study Participants Supplementary Table 3 Baseline Characteristics and Clinical Outcomes of Individual Patients Supplementary Table 4 Characteristics of UTAA06 Products Supplementary Table 5 Serum Tumor Marker Kinetics

PURPOSE:The clinical efficacies of third- or later-line therapies for metastatic colorectal cancer (CRC) are extremely limited. The purpose of this study was to evaluate the safety and efficacy of a chimeric antigen receptor T (CAR T) cell targeting guanylyl cyclase 2C (GUCY2C) that was steadily expressed in all stages of CRC in a phase I study. PATIENTS AND METHODS:This was an open-label, single-center, phase I study, consisting of a 3 + 3 pattern dose-escalation phase and a dose-expansion investigation. Tumor tissues were histologically confirmed positive for GUCY2C expression. Four dose levels were tested in the dose-escalation phase, including 3 × 108 (DL1), 6 × 108 (DL2), 12 × 108 (DL3), and 20 × 108 (DL4) CAR T cells. The primary end points were safety and tolerability within 28 days after the first infusion. RESULTS:In the dose-escalation phase, dose-limiting toxicity was not observed. DL3 was chosen for dose-expansion study. A total of 20 patients with metastatic CRC were infused with GUCY2C CAR T after lymphodepletion, and only one patient (5.0%) showed grade 3 cytokine release syndrome and neurotoxicity. Grade 3 diarrhea occurred in 11 patients (55.0%). Of 19 evaluable patients, the objective response rate (ORR) was 26.3%, with all responding patients in DL3 and DL4 groups. Of 10 patients in the DL3 group, the ORR was 40.0% and the median progression-free survival time (mPFS) was 7.0 months. Among patients showing medium-to-high GUCY2C expression in the DL3 group, the ORR achieved 50.0% and the mPFS was 9.0 months. CONCLUSION:GUCY2C CAR T showed acceptable safety profile and high response rate in patients with third- or later-line CRC, and the clinical efficacy was associated with CAR T dose level.

Esophageal cancer is a malignant tumor with high morbidity and mortality. Cisplatin is a first-line chemotherapeutic drug for the treatment of esophageal cancer. However, nearly half of the patients eventually develop acquired resistance, making cisplatin resistance a critical clinical challenge in treating esophageal cancer. Cancer-associated fibroblasts (CAFs) play a critical role in cisplatin resistance of esophageal cancer. We found that primary CAFs isolated from cisplatin-resistant esophageal cancer patients exhibited significantly elevated S100A4 protein levels and enhanced resistance to cisplatin. Thus, the high expression of S100A4 in CAFs is suggested to be closely linked to cisplatin resistance in clinical esophageal cancer. Herein, we designed a CREKA-Lipid@Fe-siS100A4 (C-L@F-siA4) system that can efficiently target and eliminate the S100A4 gene within CAFs. In vitro and in vivo experiments demonstrated the ability of C-L@F-siA4 to reverse the resistance and restore the effectiveness of cisplatin in treatment of esophageal cancer. This study provides a target for treating esophageal cancer with acquired cisplatin resistance and offers a strategy as an adjuvant method for chemotherapy of esophageal cancer.

Supplementary Figure 1 Specificity profiling of the anti-B7-H3 scFv using the Membrane Proteome Array (MPA). Supplementary Figure 2 Study Dose-Escalation Schema. Supplementary Figure 3 Association of Peak CAR-T Cell Expansion (Cmax) with Clinical Outcomes. Supplementary Figure 4 Lymphocyte Reconstitution Dynamics Following UTAA06 Infusion. Supplementary Figure 5 Longitudinal Serum Cytokine Dynamics Following UTAA06 Infusion. Supplementary Figure 6 Association of Cytokine Fold-Change with Clinical Outcomes. Supplementary Figure 7 Host CD8+ Activation and CAR-T Copy Number Kinetics for Individual Patients. Supplementary Figure 8 Longitudinal analysis of NK cell activation and inhibitory markers in patient P10.

Helicobacter pylori (H. pylori) infection is associated with enhanced efficacy of immunotherapy in gastric cancer (GC). However, the mechanisms underlying this enhancement are not fully understood. We recruited 218 GC patients, 134 esophageal squamous cell carcinoma (ESCC) patients, and 86 dMMR/MSI-H colorectal cancer (CC) patients and collected their stool and tumor samples to analyze the gut and intratumoral microbiome. We assessed microbial diversity and composition and correlated these findings with clinical outcomes to evaluate the relationship between H. pylori status, microbiome alterations, and immunotherapy efficacy. H. pylori-positive patients showed higher alpha diversity and unique microbial signatures, which were associated with increased immune-related progression-free survival (irPFS) and overall survival (irOS). In addition, we found that the abundance of 45 gut microbiome species was significantly different between the two groups. The gut microbiome of the H. pylori-positive GC group was enriched with species such as Clostridium leptum, Oscillibacter sp. ER4, and Ruminococcus bromii, which were associated with improved treatment response. However, they predicted poor prognosis in patients with esophageal squamous cell carcinoma and colorectal cancer patients with dMMR/MSI-H. Microbial co-occurrence network revealed significantly distinct interaction patterns among the groups. In addition, we found enhanced l-arginine biosynthesis in the gut microbiome of H. pylori-positive GC. In terms of intratumoral bacteria, we identified two genera, Streptococcus and Granulicatella, that were mutually exclusive with H. pylori infection in GC. Enhanced l-lysine fermentation to acetate and butanoate was observed among intratumoral bacteria, suggesting potential metabolic shifts in the tumor microenvironment. Incorporating H. pylori infection status into the microbiome-based prediction model further improved the accuracy of predicting immunotherapy outcomes in GC. These findings suggest that H. pylori had significant effects on the structure and functional activity of gut and intratumoral microbiome, some of which may affect the efficacy of immunotherapy. The clinical value of H. pylori infection status should be considered when establishing a prediction model for immunotherapy efficacy based on gut microbiome.

2557 Background: Claudin18.2 (CLDN18.2) has emerged as a new target for the treatment of gastric cancer in the first-line (1L) setting with the approval of zolbetuximab. This long-term analysis reports the extended efficacy and safety of satri-cel (autologous CLDN18.2-specific CAR T cells) as sequential therapy after 1L treatment in patients with advanced gastric/gastroesophageal junction (G/GEJ) cancer, after the results of all cohorts published in 2024 (Qi C, et al. Nat Med. 2024;30(8):2224-2234. NCT03874897). Methods: This trial is an open-label, multi-cohort, phase 1 trial, which evaluated the safety and efficacy of satri-cel in patients with CLDN18.2-positive advanced gastrointestinal cancers. Cohort 3 in dose-expansion stage enrolled patients with advance G/GEJ cancer and were given satri-cel as sequential treatment after 1L therapy. The primary endpoint was safety; secondary endpoints included efficacy, pharmacokinetics and immunogenicity. Results: As of October 18, 2025, 5 patients with CLDN18.2-positive G/GEJ cancer received satri-cel infusion(s) of 250×106 cells, sequentially after 1L therapy. Each patient received a total of one (n=1), two (n=1), and three doses (n=3) of satri-cel. Patients had received a median of 5 cycles (range, 4-11) of 1L chemotherapy before satri-cel infusion, with 1 (20%) treated with PD-1 inhibitor. Notably, only 1 patient achieved PR after first-line therapy. Three patients (60%) were Lauren diffuse type and 1 (20%) with mixed type, 4 (80%) had signet ring cell carcinoma, and 4 (80%) had peritoneal metastases. Median follow-up from initial 1L therapy was 54.6 months (reverse KM, 95% CI: 51.1, NE). Among 4 patients with target lesions, confirmatory objective response rate was 100%, and median duration of response was not reached. One has maintained SD for 20.9 months and 2 received surgical resection after satri-cel therapy. Median progression-free survival and median overall survival since 1L therapy was 20.9 months (95% CI: 10.8, NE) and 22.1 months (95% CI: 10.8, NE), respectively. Two were still alive as of cutoff date, with a follow-up of 58.1 months and 51.1 months. Safety was manageable. No grade 3 or higher cytokine release syndrome (grade 1: n=1, 20%; grade 2: n=4, 80%), any grade immune effector cell-associated neurotoxicity syndrome, or treatment-related deaths occurred. Despite common hematologic toxicities, no severe infections (grade ≥3) or febrile neutropenia were reported. Conclusions: With an extended follow-up exceeding 4.5 years, satri-cel as first-line sequential treatment continues to demonstrate durable survival benefit with a manageable safety profile in patients with advanced G/GEJ cancer, supporting its highly promising potential in earlier lines of therapy. Clinical trial information: NCT03874897 .

PURPOSE:Despite emerging genomic discoveries, few have been translated into practical management strategies for people with gastroenteropancreatic neuroendocrine carcinoma (GEPNEC). This study aims to identify key genes and their potential clinical relevance to improve care for this patient group. METHODS:In the analytical cohort, we reported high-frequency alteration genes, significantly mutated genes, and driver genes and defined their overlap as key genes. Genotypes were identified as Type I/II/III. For further validation, we prospectively recruited eligible patients to build a main cohort, through which we performed univariate/multivariate Cox regression analysis and sketched Kaplan-Meier survival plot. Targetable genes were defined by the OncoKB database. RESULTS:The analytical cohort consisted of 124 patients. The genes most frequently altered were TP53 (78%), RB1 (35%), APC (27%), and KRAS (17%). Key genes were identified as TP53, RB1, APC, and KRAS. The main cohort included 171 patients. We defined the genotype "Type I" (defined as TP53/RB1 co-alterations) as a reference. In midgut/hindgut NEC, we identified a "Type II" subtype characterized by mutations in either APC or KRAS alterations without TP53/RB1 co-alterations. Type II of midgut/hindgut NEC patients had elevated carcinoembryonic antigen (CEA) levels and longer median overall survival (mOS) than others (not reached vs 11.4 months, HR = 0.19[0.08, 0.44], P = .0028). In foregut NEC, we identified "Type III" (either APC/KRAS alterations or TP53/RB1 co-alterations). Type III of foregut NEC patients showed shorter mOS than others (11.6 vs 19.0 months, HR = 1.93[1.13, 3.25], P = .01). Type II patients who received non-platinum/etoposide (EP) chemotherapy had longer first-line progression-free survival (PFS) compared to EP regimen. They also benefited from second-line immunotherapy. Targeted therapy as second-line was also suitable for targetable patients (longer PFS than others: 12.5 vs 3.0 months, HR = 0.40[0.21-0.75], P = .0017). CONCLUSIONS:Our study identified key gene-based genotypes (Type II/III) of distinct GEPNEC patients and yielded their prognosis and therapeutic utility.

4055 Background: Chemotherapy for advanced esophageal squamous cell carcinoma (ESCC) is limited due to the lack of effective drugs. Such as traditional two drugs chemotherapy (5-Fluorouracil and Cisplatin) as first-line treatment for metastatic and recurrent ESCC has an efficacy of 25-35%. Nimotuzumab is an anti-epidermal growth factor receptor (EGFR) monoclonal antibody. Previous studies have shown that its combination with paclitaxel and cisplatin (TP regimen) has a good efficacy, with an objective response rate (ORR) of up to 55%, median overall survival (mOS) 13.9 months in some small-sample trials. Methods: Eligible patients from 36 centers in China, who were randomly assigned to receive nimotuzumab (400 mg once per week, up to 2 years) or placebo followed by TP regimen (paclitaxel 175 mg/m², cisplatin 60 mg/m², Day 1, with a 21-day cycle, up to 6 cycles) until disease progression or unacceptable toxicity. The primary end point was overall survival (OS) and the secondary end points were progression-free survival (PFS), response rates, quality of life (QoL) and safety. Results: A total of 640 patients were screened. 503 patients were enrolled and 161 patients with EGFR gene amplification tumors were eligible. In the full analysis set of 497 patients who had took at least one dose of medication, there were no differences in baseline characteristics. The mOS were 12 vs 11.5 months, and the median PFS were 5.6 vs 5.4 months respectively, suggesting survival benefit trend in the trial. ORR were 55.5% and 50.4% for both arms. In the EGFR gene amplification subgroup, the mOS was 13.3 vs 9.5 months (log-rank test, hazard ratio [HR] = 0.66 (95%CI, [0.47-0.93]), P = 0.016) for two groups. Patients who were with ESCC at stage IV, as well as who had not undergone surgery, radical radiotherapy, or neoadjuvant and adjuvant therapy showed significant survival benefits after the addition of nimotuzumab. Median PFS were 6.0 vs 5.5 months for two arms (log-rank test, HR = 0.63 [0.43-0.91], P = 0.014). Both OS and PFS were longer in the nimotuzumab group than in the placebo group. The ORR of the two groups were 61.3% and 44.0%, respectively (P = 0.029). There were no statistically significant differences in the QoL scores of the FAS population at each time point before and after treatment. The incidence of adverse events were comparable in the experimental group and the control group. Such as the incidence of serious adverse event (SAE) was 30.7% and 34.5%, serious adverse drug reaction (SADR) was 2.7% and 8.3%, the incidence of above grade 3 treatment emergent adverse event (TEAE) was 85.3% and 83.3%, respectively, etc. Conclusions: In patients with metastatic EGFR gene amplification ESCC, nimotuzumab plus TP as first-line treatment significantly improved OS and PFS with a good safety profile.

BACKGROUND:Immune checkpoint inhibitors (ICIs) are known for their durable efficacy and favorable tolerance profiles. However, elderly patients are often underrepresented in clinical trials. The manifestation of immune-related adverse events (irAEs) in elderly patients with different tumor types remains unclear. This study aimed to compare irAEs in elderly patients with gastrointestinal and lung cancers receiving ICIs and to provide real-world safety data. METHODS:This retrospective study included elderly patients (≥70 years) with gastrointestinal (GI) tumors or lung cancer who received ≥2 cycles of ICIs across multiple departments within a single academic medical center between January 2016 and February 2022. A 2:1 propensity score matching was used to balance baseline characteristics between the cohorts. The primary endpoint was the incidence of any-grade irAEs between GI tumors and lung cancer, whereas secondary analyses focused on organ-specific toxicities. Statistical comparisons were performed using the chi-squared test. RESULTS:The overall incidence of any-grade irAEs was higher in elderly patients with lung cancer than in those with GI tumors (61.0% vs . 47.9%; P = 0.013). After matching for baseline characteristics, the lung cancer group still showed a trend toward a higher incidence of irAEs (61.7% vs . 50.8%; P = 0.056). Notably, patients with GI tumors had a higher incidence of skin toxicity (28.7% vs . 15.1%; P = 0.002), whereas patients with lung cancer had a higher incidence of thyroid dysfunction (28.1% vs . 11.9%, P <0.001). CONCLUSIONS:Elderly patients with lung cancer were more likely to experience irAEs during immunotherapy than those with GI tumors. However, dermatological toxicities were more common in elderly patients with GI tumors, whereas thyroid dysfunction was more frequently observed in those with lung cancer.

Abstract Purpose: The aim of the study was to evaluate the safety, pharmacokinetics, and preliminary clinical activity of UTAA06, an “off-the-shelf” allogeneic B7-H3–targeted chimeric antigen receptor (CAR) Vδ1T-cell therapy, in patients with pretreated, advanced B7-H3–positive solid tumors. Patients and Methods: In this first-in-human, phase I, dose-escalation study (NCT06372236), 10 patients with advanced solid tumors (including gastric, colorectal, hepatocellular, ovarian, and neuroendocrine cancers) were enrolled. Following lymphodepletion chemotherapy (cyclophosphamide and fludarabine), patients received UTAA06 infusion across three dose levels (5 × 108, 8 × 108, or 1 × 109 cells). The primary endpoint was safety. Secondary endpoints included pharmacokinetics and antitumor efficacy. Results: UTAA06 demonstrated a manageable safety profile; no GVHD was observed, and cytokine release syndrome was limited to two transient grade 1 events. A single dose-limiting toxicity (grade 3 pneumonitis) was reported in one patient at the 5 × 108 cell dose level. Although UTAA06 demonstrated signals of biological activity, including transient reductions in serum tumor markers in 50% of patients, no objective response by RECIST v1.1 criteria was observed. Further analysis identified that the limited CAR T-cell persistence was likely driven by subclinical host-versus-graft rejection. Conclusions: This study provides clinical proof of concept for allogeneic B7-H3–targeted CAR-Vδ1T cells as a safe platform with low risk of GVHD and demonstrable biological activity in solid tumors. However, clinical efficacy was constrained by limited cellular persistence caused by host immune rejection. Future strategies are required to enhance the durability and therapeutic potential of this allogeneic approach.

4008 Background: Chemotherapy plus a PD-1/PD-L1 inhibitor is the standard first-line treatment for PD-L1 expressing advanced ESCC. However, most patients (pts) inevitably develop resistance to first-line therapy, and second-line chemotherapy shows an ORR of less than 10% and a median OS of less than 6 mo, highlighting the urgent need for novel therapeutics. Iza-bren is a potentially first-in-class ADC consisting of an EGFR-HER3 bispecific antibody conjugated to a potent topoisomerase I inhibitor Ed-04 via a cleavable linker. Iza-bren has shown promising clinical activity in previously treated ESCC pts in phase I study. Here, we present results from a phase III, randomized, open-label, multicenter study conducted in China evaluating the efficacy and safety of iza-bren versus chemotherapy as second line treatment for advanced ESCC. Methods: Pts with recurrent or metastatic ESCC who had progressed after first-line treatment with a PD-1/PD-L1 inhibitor plus platinum-based chemotherapy were randomized (1:1) to receive iza-bren (2.5 mg/kg at D1D8 Q3W) or physician’s choice of chemotherapy (irinotecan, paclitaxel, or docetaxel Q3W). Dual primary endpoints were OS and PFS by Blinded Independent Central Review (BICR) per RECIST v1.1. Results: As of Oct 17, 2025, a total of 497 pts were randomized to iza-bren (n = 249) or chemotherapy (n = 248). Baseline characteristics were balanced between the two groups. At interim analysis, median follow-up for OS was 7.8 mo in the iza-bren group and 7.6 mo in the chemotherapy group. Iza-bren has demonstrated statistically significant and clinically meaningful improvement in both OS and PFS by BICR compared with chemotherapy. The median OS was 9.8 mo (95% CI, 7.9 to 11.0) with iza-bren and 7.2 mo (95% CI, 6.2 to 8.2) with chemotherapy (HR, 0.64; 95% CI, 0.49 to 0.83; P = 0.0004). The median PFS by BICR was 4.2 mo (95% CI, 3.6 to 4.5) with iza-bren and 2.0 mo (95% CI, 1.6 to 2.7) with chemotherapy (HR, 0.50; 95% CI, 0.40 to 0.63; P < 0.0001). ORR by BICR was 35.3% for iza-bren and 13.1% for chemotherapy. Grade≥3 TRAEs, which were predominantly hematologic in nature, occurred in 85.1% in the iza-bren group and 60.2% in the chemotherapy group. TRAEs leading to drug discontinuation were 2.0% in the iza-bren group and 3.3% in the chemotherapy group. TRAEs leading to death were 1.2% in the iza-bren group and 1.6% in the chemotherapy group. Conclusions: The study met both dual primary endpoints at prespecified interim analysis. Iza-bren demonstrated statistically significant and clinically meaningful improvements in OS and PFS compared with chemotherapy in pts with recurrent or metastatic ESCC who had progressed after first line PD-1/PD-L1 inhibitor plus platinum-based chemotherapy. The safety profile was manageable. The results support iza-bren as a new second-line standard of care for ESCC. Clinical trial information: NCT06304974 .

Research on patients with advanced esophageal squamous cell carcinoma (ESCC) who have progressed on immunotherapy remains limited. BL-B01D1 is a first-in-class antibody-drug conjugate consisting of an EGFR-HER3 bispecific antibody bound to a topoisomerase I inhibitor (Ed-04) payload via a cleavable linker. Here, we present safety and efficacy data from a phase 1 study of BL-B01D1, in 82 patients previously treated for ESCC. The primary endpoint was the recommended phase 2 dose. Administered doses were 2.0 (n = 22) and 2.5 (n = 60) mg kg-1 D1D8 infusion every 3 weeks (Q3W). The confirmed objective response rate (cORR) was 29.3% (24 of 82) in all patients and 32.9% (24 of 73) among evaluable patients. For patients dosed at 2.5 mg kg-1, cORR was 39.6% (21 of 53) and disease control rate was 79.2% (42 of 53). In the 2.0 mg kg-1 group, cORR was 15.0% (3 of 20), and the disease control rate was 50.0% (10 of 20). The phase 2 dose was established at 2.5 mg kg-1 D1D8 Q3W. The incidence of G3 treatment-related adverse events at 2.5 mg kg-1 was 63.3%; most common adverse events were anemia (28.3%), leukopenia and thrombocytopenia (18.3%, each), and neutropenia (16.7%). Two cases of ≥G3 interstitial lung disease were observed. Overall, BL-B01D1 demonstrated promising efficacy and manageable safety in patients with metastatic ESCC. A further phase 3 clinical trial has already been initiated. ClinicalTrials.gov registration: NCT05262491 .

4016 Background: Challenges persist in the treatment of aEC, particularly for pts with esophageal stenosis and dysphagia, conditions that deteriorate the nutrition status and hinder anti-tumor therapies, leading to dismal prognosis. Building on the promising anti-tumor activity and improvement in dysphagia in a phase II single-arm trial, the phase III DYNA-Esophagus03 trial assessed DVDMS, a novel photosensitizer, -mediated PDT in aEC, comparing to TPC. Methods: Pts with local recurrence or metastasis EC and Stoller dysphagia grade ≥2, stratified by previous treatment lines (1 st vs 2 nd -line), were randomized 2:1 to DVDMS-mediated PDT (PDT delivered 24 hours after 0.2 mg/kg DVDMS injection at a light dose of 102 J/cm² and wavelength of 630±5 nm) or TPC. The primary endpoint was esophageal stenosis overall response rate (es-ORR) assessed by endoscopy at 28 days. A sample size of 186 pts achieved a 90% power to detect an es-ORR increase from 10% to 35% at a 1-side 2.5% level, considering a 30% drop-off rate. Results: As of November 11, 2024, 186 pts were randomly assigned (124 DVDMS-PDT group/62 TPC group). The baseline characteristics were: mean age 67.6 ± 8.7 years, 32.3% distant metastasis, 52.2% grade 3 dysphagia, and 1.1% grade 4. The es-ORR was 51.6% with DVDMS-PDT vs 8.1% with TPC at day 28 (P < 0.0001). At a median follow-up of 8.9 months (mos), the median progression-free survival was 2.8 vs 2.2 mos (HR = 0.61, 95%CI 0.40-0.93; P = 0.0244), respectively. Time to progression was 5.9 vs 3.9 mos (HR = 0.45, 95% CI: 0.25-0.82, P = 0.0056). Median overall survival (OS) was 7.0 vs 6.4 mos (HR = 0.88, 95%CI 0.59-1.32; P = 0.5169), respectively. Considering the high cross-over rate (45.2%), the rank preserving structural failure time-adjusted median OS was 7.0 vs 4.7 mos (HR = 0.64, 95%CI 0.42-0.97; P = 0.0223). The improvement of dysphagia and quality of life are detailed in the Table. Phototoxicity was negative in 64.9% pts in DVDMS-PDT group on day 7, increasing to 91.4% by day 28. Grade ≥3 treatment-emergent adverse events occurred in 38.2% of the DVDMS-PDT group and 49.2% of the TPC group. Six deaths were due to treatment-related adverse events (4.9%) were reported in the DVDMS-PDT group and 5 (8.5%) in the TPC group. Conclusions: DVDMS-PDT significantly improved esophageal stenosis and dysphagia compared to the treatment of physician’s choice in pts with aEC, with prolonged PFS and TTP, potential better OS and a manageable safety profile. Clinical trial information: CTR20221271 . DVDMS-PDT (n=124) TPC (n=62) Reduction at least 1 grade in Stooler's score in 6 mons, % 47.8% 8.6% (P<0.0001) Change in EORTC QLQ-C30 total score -26.7 ± 2.5 -39.8 ± 4.3 Change in dysphagia score 16.0 ± 2.6 24.6 ± 4.3 Change in eating score 16.9 ± 2.4 30.6 ± 4.1 Values are least-squares mean ± standard error unless otherwise noted. Symptom scores were assessed using EORTC QLQ-OES18.

e16007 Background: Esophageal squamous cell carcinoma (ESCC) is a highly aggressive malignancy with limited treatment options, particularly in patients who develop resistance to immune checkpoint inhibitors (ICIs). The development of cancer vaccines capable of inducing robust and durable T cell responses represents a promising strategy to overcome these challenges. Here, we describe a universal, multi-epitope mRNA-lipid nanoparticle (LNP) vaccine targeting tumor-associated antigens (TAAs) commonly expressed in ESCC and investigate its immunogenicity, antitumor efficacy, and potential synergy with PD-1 blockade in preclinical models. Methods: TAAs were identified through transcriptomic analysis of The Cancer Genome Atlas (TCGA) and Genotype-Tissue Expression (GTEx) datasets, and validated in ESCC patient samples. The mRNA vaccine was optimized for stability and antigen presentation and tested in HLA-A2.1 and HLA-A11.1 transgenic mouse models. Antigen-specific immune responses were assessed using ELISPOT and flow cytometry. Therapeutic efficacy was evaluated in prophylactic and therapeutic tumor models with or without PD-1 blockade. Tumor-infiltrating immune cells were characterized using immunohistochemistry and single-cell RNA sequencing. Results: In both HLA-A2.1 and HLA-A11.1 transgenic mice, the vaccine induced measurable immune responses for most antigen fragments, with ELISPOT assays showing significant IFN-γ secretion in response to peptide pools (p < 0.001 vs. control). In prophylactic models, tumor incidence was reduced by 100% (p < 0.001). In therapeutic models, tumor growth was significantly suppressed, and median survival increased to 44.5 days compared to 31 days in the control group (p < 0.05). Combination therapy with PD-1 blockade further enhanced tumor control, achieving a tumor reduction rate of 85%, and increased the infiltration of cytotoxic CD8+ T cells by 3.4-fold. Single-cell RNA sequencing revealed clonal expansion of T cells and reprogramming of the tumor microenvironment toward a more immunogenic state. Conclusions: This multi-epitope mRNA-LNP vaccine induces robust, durable T cell responses and effectively suppresses tumor growth in ESCC models. Its combination with PD-1 blockade further enhances antitumor efficacy by overcoming immune resistance and reshaping the tumor microenvironment. These findings provide a strong rationale for advancing this vaccine strategy into clinical trials to improve outcomes in patients with ESCC.

This individual patient data pooled analysis aimed to evaluate the effectiveness, safety, and patterns of use of camrelizumab in a large cohort of advanced esophageal cancer (AEC) patients. Adult patients (≥ 18 years) who had received camrelizumab as part of AEC treatment were pooled from three independent, prospective observational cohort studies (NCT04616040, ChiCTR1900027275, and ChiCTR2000039499). The main outcomes were patterns of camrelizumab use, progression-free survival (PFS), overall survival (OS), and safety in the overall population and specific subgroups of underrepresented patients. Among 987 patients, 450 (45.6