BACKGROUND:FOLFIRINOX is a standard first-line therapy for metastatic pancreatic ductal adenocarcinoma (PDAC), but its toxicity often necessitates dose adjustments. This study evaluated the impact of first relative dose intensity (RDI) of irinotecan and oxaliplatin on treatment outcomes and safety in PDAC patients. METHODS:This retrospective multi-center cohort study included 109 PDAC patients treated with FOLFIRINOX across 12 Taiwanese hospitals from 2017 to 2020. Initial RDI was defined as the ratio of actual to standard doses of irinotecan and oxaliplatin in the first cycle. Patients were categorized into three RDI groups: <70%, 70-90%, and ≥90%. RESULTS:The median PFS was 5.1 months and median OS was 11.6 months. In the <70%, 70-90%, and ≥90% RDI groups, median PFS was 4.9, 7.1, and 3.5 months, and median OS was 10.7, 16.2, and 7.0 months, respectively. The 70-90% group had significantly longer OS than the <70% and ≥90% groups and PFS in the 70-90% group was significantly longer than in the ≥90% group. Grade ≥3 adverse events occurred in 49.5% of patients, mainly hematologic. The ≥90% group had the highest toxicity despite receiving a median of 3.5 cycles. CONCLUSION:The initial RDI of 70-90% for irinotecan and oxaliplatin may optimize both efficacy and tolerability in Taiwanese PDAC patients treated with FOLFIRINOX.

Abstract Background: Claudin 18.2 (CLDN18.2) is a transmembrane tight junction protein with expression restricted to the gastric mucosal epithelia where CLDN18.2 protects against paracellular acid leakage and associated gastritis.1 CLDN18.2 overexpression has been observed in several tumor types, including gastric, esophageal, and pancreatic cancer.2,3 Loss of cell polarity in these tumors results in CLDN18.2 localization to surfaces that are more readily accessible to biologics and effector cells. This expression pattern makes CLDN18.2 a compelling target for immune-stimulating antibody conjugates (ISACs) that combine the specificity of tumor-targeting antibodies with the potency and durability of immune activation. BDC-4182 is a next-generation ISAC consisting of a CLDN18.2-targeting antibody covalently attached to a novel toll-like receptor (TLR)7/8 agonist via a non-cleavable linker. In preclinical models, systemic delivery of ISACs has been shown to broadly activate the innate and adaptive immune system, leading to complete tumor regression. A BDC-4182 surrogate induced immunologic memory and epitope spreading as evidenced by rejection of tumor cells that no longer express the target antigen (CLDN18.2) following re-challenge.4,5 Methods: This is a first-in-human Phase 1 dose escalation and Phase 2 expansion study of BDC-4182. Up to 122 patients with advanced gastric and gastroesophageal cancer will be enrolled. To optimize tolerability, BDC-4182 is administered via an intra-patient step-up dosing regimen wherein subjects receive lower initial priming doses prior to the target dose. Primary objectives are to define safety and tolerability and to determine the recommended phase 2 dose (RP2D) of BDC-4182 as a single agent. Secondary objectives will evaluate the preliminary anti-tumor activity of BDC-4182, analyze PK characteristics of BDC-4182, and evaluate the immunogenicity of BDC-4182 as a single agent. Exploratory analyses will also be conducted to explore potential biomarkers in blood and tumor tissue associated with exposure, efficacy, or safety of BDC-4182, and to define CLDN18 expression in tumor tissue. This study is being conducted in Australia, South Korea, and Taiwan. References: 1. Suzuki K, Sentani K, Tanaka H, et al. Cell Mol Gastroenterol Hepatol. 2019;8:119-142. 2. Hong JY, An JY, Lee J, et al. Transl Cancer Res. 2020;9:3367-3374. 3. Chen J, Xu Z, Hu C, et al. Front Oncol. 2023;13:1132319.4. Fu C, Luo A, Liu J, et al. J Immunother Cancer. 2024;12(Suppl 2):Abstract 1052. 5. Kim HK, Monnier J, Fu C, et al. J Immunother Cancer. 2023;11(Suppl 1):Abstract 1147-D. Citation Format: Sophia Frentzas, Michelle Morris, Megan Barnet, Niall Tebbutt, Mark Wong, Michael Michael, Hyung-Don Kim, Keun-Wook Lee, Sun Young Rha, Sang Cheul Oh, I-Chen Wu, Li-Yuan Bai, Wen-Chi Chou, Ming-Huang Chen, Yen-Yang Chen, Chia-Chi Lin, Anthony Rodrigues, Jason Ptacek, Michael N. Alonso, Tariq Arshad, Jakob Dupont, Kristi Balacy, Sung Hee Lim. A Phase 1/2 study of BDC-4182, a claudin18.2-targeting next generation immune-stimulating antibody conjugate (ISAC), in patients with advanced gastric and gastroesophageal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(8_Suppl):Abstract nr CT094.

Gastric cancer (GC) remains a global health burden. While international guidelines share consensus, variations exist in disputed issues. The 2025 Taiwan Consensus and Management Guidelines for Gastric Cancer had just been released. We compared the key recommendations with established international guidelines. A multidisciplinary taskforce addressed key questions and recommendations using modified Delphi method and evidence-based approaches. The comparative review aimed to elucidate similarities and differences among guidelines from Taiwan, Japan, South Korea, China, Europe, and the US. Guidelines converge on absolute endoscopic resection criteria for early GC but differ in extended indications and perioperative approaches for locally advanced disease. Heterogeneity exists in biomarker assessment protocols, cutoff thresholds, and companion diagnostics. For metastatic disease, consensus exists on anti-HER2, anti-VEGF, immunotherapy, and biomarker-driven strategies, though oligo-metastatic definitions and intraperitoneal chemotherapy indications remain controversial. Optimal GC management requires integrating global evidence with regional contexts. The comparative review addresses heterogeneity among international guidelines, which helps harmonize management strategies as therapeutic standards evolve.

TPS2689 Background: Advanced solid tumors frequently exhibit resistance to standard therapies, including immune checkpoint inhibition. Intratumoral Tregs have been associated with immune suppression, tumor progression and anticancer resistance. Intratumoral Tregs preferentially express CCR8 and are abundant in many solid tumors (Plitas 2020; Plitas 2016; Kidani 2022). Tagmokitug is a novel, selective cytolytic anti-CCR8 mAb designed to deplete CCR8+ Tregs and remodel the tumor microenvironment to promote antitumor immunity. Preclinical and phase 1 clinical studies show tagmokitug can significantly deplete CCR8+ intratumoral Tregs, increase immune activation and has antitumor activity in combination with a PD-1 inhibitor (Wang 2026; Worden 2025; Kapoor 2025). These findings warrant evaluation of tagmokitug in combination with toripalimab, a PD-1 inhibitor, and/or other anticancer therapies across multiple tumor types. Methods: This multicenter, open-label, phase 1b/2a study evaluates tagmokitug in combination with toripalimab and/or other therapies in adults with advanced solid tumors in 4 cohorts: gastric, gastroesophageal junction (GEJ), and esophageal adenocarcinoma; second-line esophageal squamous cell carcinoma (ESCC); first-line ESCC; and advanced MSS/pMMR colorectal cancer. Eligible participants have histologically or cytologically confirmed advanced or metastatic solid tumors not amenable to curative therapy, measurable disease per RECIST v1.1, ECOG 0–1, and adequate organ function. Key exclusions include active autoimmune disease requiring systemic therapy, uncontrolled cardiovascular conditions, or other factors interfering with study participation. Tagmokitug is administered IV Q3W at pharmacologically active doses following toripalimab 240 mg IV and/or other anticancer therapies where indicated per protocol. Imaging assessments are performed every 6 weeks through week 24, every 9 weeks through week 51 and every 12 weeks through week 99. Patients continue treatment until disease progression, unacceptable toxicity, or withdrawal of consent. The primary objective is to evaluate the safety and tolerability of tagmokitug in combination with toripalimab and/or other anti-cancer therapies as measured by adverse events and laboratory abnormalities. Secondary endpoints include ORR, DOR, DCR, and PFS per RECIST v1.1, and assessment of PK and ADA. Exploratory endpoints include OS and biomarker analyses including evaluation of CCR8+ Tregs in tumors. Enrollment is ongoing. Approximately 150 participants are planned across all cohorts. Additional cohorts may be added based on emerging data. Clinical trial information: NCT06657144 .

4010 Background: In HERIZON-GEA-01 (NCT05152147), 1L zanidatamab + CT ± tislelizumab significantly improved progression-free survival (PFS) and, with tislelizumab, yielded a statistically significant overall survival (OS) benefit in HER2+ mGEA. Here we report efficacy in PD-L1 subgroups. Methods: Eligible patients (pts) with previously untreated HER2+ mGEA, irrespective of PD-L1 status, were randomized (1:1:1) to zanidatamab (1800 mg [<70 kg]/2400 mg [≥70 kg] IV Q3W) + tislelizumab (200 mg IV Q3W) + capecitabine/oxaliplatin (CAPOX) or 5-FU/cisplatin (FP); zanidatamab + CAPOX or FP; or tras + CAPOX or FP. PD-L1 expression was retrospectively assessed using the VENTANA SP263 assay according to tumor area positivity (TAP) score and combined positive score (CPS). Primary endpoints were PFS (BICR) and OS; efficacy by PD-L1 status (TAP) was prespecified. Results: With 26 mo median follow-up, PFS (HR, 0.63; P <0.001) and OS (HR, 0.72; P = 0.004) were significantly prolonged with zanidatamab + tislelizumab + CT vs tras + CT in the ITT population. In pts treated with zanidatamab + tislelizumab + CT, similarly prolonged PFS and OS were observed in PD-L1–negative and PD-L1–positive pts (Table); data were consistent between TAP and CPS. In PD-L1 TAP <1% and ≥1% pts, the 18-mo PFS was 50.3% and 42.6%, respectively, and the 24-mo OS was 63.7% and 53.5% with zanidatamab + tislelizumab + CT. In the tras + CT arm, OS was prolonged in PD-L1–positive vs –negative pts. Of note, in the tras + CT arm, 15% of pts received subsequent checkpoint inhibitors and 29% received subsequent HER2-targeted therapies vs 2% and 13%, respectively, in the zanidatamab + tislelizumab + CT arm. Additional details on these subgroups will be presented at the congress. Conclusions: In HERIZON-GEA-01, zanidatamab + tislelizumab + CT demonstrated meaningful improvements in PFS and OS in both PD-L1–positive and PD-L1–negative pts as determined by TAP or CPS. The longer OS observed with tras + CT in PD-L1–positive vs –negative pts may be at least partially explained by differences in subsequent therapies. These findings are notable as they demonstrate benefit for this regimen regardless of PD-L1 status. Clinical trial information: NCT05152147 . Zanidatamab + Tislelizumab + CT Tras + CT ITT NmPFS (95% CI), momOS (95% CI), mo 30212.4 (9.8, 18.5)26.4 (21.5, 30.3) 3088.1 (7.0, 8.9)19.2 (16.8, 21.8) TAP <1%n (%)mPFS (95% CI), momOS (95% CI), mo 90 (29.8)18.5 (9.7, 25.2)29.7 (24.7, NE) 98 (31.8)7.9 (5.8, 9.6)15.8 (12.6, 21.4) CPS <1n (%)mPFS (95% CI), momOS (95% CI), mo 78 (25.8)18.5 (9.7, 25.2)30.3 (25.7, NE) 80 (26.0)8.1 (5.8, 9.8)15.7 (12.6, 21.4) TAP ≥1%n (%)mPFS (95% CI), momOS (95% CI), mo 187 (61.9)11.3 (9.6, 18.5)26.4 (18.7, 35.9) 188 (61.0)8.3 (6.9, 9.7)21.2 (17.7, 25.2) CPS ≥1n (%)mPFS (95% CI), momOS (95% CI), mo 198 (65.6)12.3 (9.7, 18.5)26.4 (18.7, 34.6) 206 (66.9)8.2 (6.9, 9.1)20.8 (17.3, 23.9)

Oral squamous cell carcinoma (OSCC) is one of the leading causes of cancer‐related mortality in Taiwan. Natural products have long served as a valuable source of chemotherapeutic agents. In the present study, we investigated the antitumor effects of DOK, a diterpene derived from Adenostemma lavenia , a plant traditionally used an herbal tea, in OSCC cells. DOK markedly suppressed cell growth in SCC2095 and SCC4 cells, with IC 50 values of 4.0 and 3.4 μM, respectively, after 48 h of treatment, while exhibiting substantially lower cytotoxicity in human oral fibroblasts. Flow cytometric analysis and immunoblotting revealed that DOK activates caspase‐dependent apoptotic signaling in OSCC cells. In addition, DOK was associated with alterations in Akt/mTOR and MAPK signaling pathways. Autophagy‐related responses following DOK treatment were evidenced by the accumulation of autophagosome‐like structures in SCC2095 cells, as observed by confocal microscopy and acridine orange staining, together with increased expression of LC3B‐II and p62. Pharmacological inhibition of autophagy using chloroquine (CQ) enhanced DOK‐induced cytotoxicity, supporting the involvement of autophagy‐related responses and an association between DOK treatment and altered autophagic flux. Collectively, these findings demonstrate the multifaceted anticancer activities of DOK and highlight the therapeutic potential of A. lavenia –derived compounds for OSCC treatment.

BACKGROUND Pathologic complete response is rarely achieved in metastatic gastric cancer, particularly after progression on standard systemic therapy. Gamma delta (gamma delta) T cells recognize tumor cells in a major histocompatibility complex-independent manner and may enhance the antitumor effects of complement chemotherapy. CASE SUMMARY A 58-year-old man with gastric adenocarcinoma was found to have peritoneal metastases at the time of surgery and underwent palliative subtotal gastrectomy. He received first-line capecitabine/oxaliplatin plus nivolumab for approximately 6 months but subsequently developed new hepatic metastasis and progressive lymphadenopathy. Second-line therapy with ramucirumab plus paclitaxel was discontinued after two cycles because of peripheral neuropathy. The patient was then treated with ramucirumab plus trifluridine/tipiracil combined with autologous gamma delta T-cell infusions for seven cycles. After 4 months of treatment, contrast-enhanced computed tomography demonstrated disappearance of the hepatic lesion, resolution of peritoneal metastases, and marked regression of lymphadenopathy. Liver wedge resection confirmed the absence of viable tumor cells. The patient has remained recurrence-free for more than 24 months following completion of therapy. CONCLUSION The combination of chemotherapy and autologous gamma delta T-cell infusion may achieve durable remission in selected patients with refractory metastatic gastric cancer.

BACKGROUND:Transforming Growth Factor Beta (TGFβ) plays a dual role in cancer, acting as a tumor suppressor early in disease but promoting progression and immune evasion when dysregulated. In pancreatic ductal adenocarcinoma (PDAC), TGFβ-driven desmoplasia fosters chemoresistance and immunosuppression, limiting therapeutic efficacy. NIS793, a fully human monoclonal antibody targeting TGFβ, demonstrated anti-fibrotic and immunomodulatory activity in preclinical models and early-phase trials. METHODS:We conducted a randomized, open-label, phase II study in treatment-naïve metastatic PDAC patients to evaluate NIS793 ± spartalizumab (anti-PD-1) combined with nab-paclitaxel/gemcitabine (ABRA/GEM) versus ABRA/GEM alone. Primary endpoint was progression-free survival (PFS); secondary endpoints included overall survival (OS), safety, pharmacokinetics, and biomarker analyses. Exploratory assessments included paired tumor RNA sequencing, cfDNA profiling, and plasma proteomics. RESULTS:NIS793 demonstrated target engagement and suppression of TGFβ signaling, confirmed by transcriptomic and proteomic analyses. Stromal remodeling was evident, with significant downregulation of CAF markers (ACTA2, FAP) and collagen-related signatures. Despite proof-of-mechanism, clinical efficacy was not observed: median PFS and OS were comparable or numerically worse in NIS793 arm versus control (HR for OS in NIS793+ABRA/GEM vs ABRA/GEM: 1.32; 95% CI: 0.84-2.07). Safety profile was manageable, with no unexpected toxicities. Biomarker data revealed increased expression of neutrophil-related genes post-treatment, suggesting potential induction of tumor-promoting inflammation. CONCLUSIONS:NIS793 effectively inhibited TGFβ signaling and led to stroma remodeling but failed to improve outcomes in metastatic PDAC. These findings highlight the complexity of TGFβ biology and caution against its blockade in combination with chemotherapy for PDAC. Future strategies should consider context-dependent effects of TGFβ inhibition(NCT04390763).

Purpose EP4, a key receptor in the PGE 2 axis, mediates tumor immunosuppression; the EP4 antagonist ONO-4578 plus nivolumab showed manageable safety, immune activation, and preliminary antitumor activity in previously treated gastric/gastroesophageal junction cancer (G/GEJC). This study explored whether ONO-4578 enhances the efficacy of nivolumab plus chemotherapy in unresectable advanced or recurrent G/GEJC. Patients and Methods This multicenter, double-blind, randomized phase 2 study enrolled chemotherapy-naïve patients with HER2-negative unresectable advanced or recurrent G/GEJC. Patients were randomized (2:1) to receive oral ONO-4578 or matching placebo, each in combination with nivolumab and oxaliplatin-based chemotherapy. The primary endpoint was investigator-assessed progression-free survival (PFS). Secondary endpoints included overall survival (OS), objective response rate (ORR), and safety. Results At the data cutoff, 226 patients were randomized to the ONO-4578 group (n = 150) and the placebo group (n = 76). Adding ONO-4578 significantly improved PFS (hazard ratio of 0.67; 90% confidence interval, 0.48–0.92; p-value, 0.040 [prespecified two-sided α = 0.10]), with favorable OS at a prespecified analysis with limited follow-up (hazard ratio of 0.60; 95% confidence interval, 0.37–0.96) and ORR (62.0% vs 48.7%). Exploratory subgroup analyses suggested that ONO-4578 regimen provided greater benefit in PD-L1 CPS ≥1, whereas no clear benefit in CPS <1/indeterminate patients. In an extended follow-up exploratory OS analysis with a minimum follow-up of 16.1 months, OS numerically favored ONO-4578 regimen. Common treatment-emergent adverse events in the ONO-4578 group were diarrhoea (55.7% vs 45.3%), and anaemia (55.0% vs 34.7%). Conclusion This study demonstrated promising efficacy and acceptable safety of an ONO-4578 regimen as first-line treatment for HER2-negative unresectable advanced or recurrent G/GEJC. These findings warrant confirmation in a phase 3 trial.

4007 Background: Anti-PD-1 antibodies combined with chemo are the standard 1L treatment for HER2-negative G/GEJ cancer. Prostaglandin E 2 (PGE 2 )-EP4 signaling is known to induce immunosuppressive tumor microenvironment, by inducing the differentiation of MDSCs and M2 macrophages, potentially contributing to resistance to immunotherapy. ONO-4578, an EP4 antagonist, is expected to modulate tumor immunosuppression through inhibiting the PGE 2 -EP4 signaling and to enhance the efficacy of anti-PD-1 antibody. The addition of ONO-4578 appeared to augment the efficacy of NIVO in patients with G/GEJ cancer in the previous phase 1 trial. This study aimed to evaluate the efficacy and safety of ONO-4578 combined with NIVO and chemo compared with placebo combined with NIVO and chemo as 1L treatment for patients with unresectable adv/rec G/GEJ cancer. Methods: ONO-4578-08 study is a randomized, double-blind, phase 2 trial conducted in Japan, Korea, and Taiwan. Chemo-naïve patients with HER2-negative adv/rec G/GEJ cancer were randomized in a 2:1 ratio (ONO-4578 group:placebo group), stratified by PD-L1 expression level (CPS < 5 vs CPS≥5), ECOG performance status (0 vs 1), presence of peritoneal metastasis (yes vs no). Patients in each group received ONO-4578 40 mg or placebo once daily, and all received NIVO 360 mg every 3 weeks and chemo (SOX [S-1 + oxaliplatin]/CAPOX [capecitabine + oxaliplatin]). The primary endpoint was investigator-assessed progression-free survival (PFS), powered (two-sided α = 0.10) to detect a HR of 0.65 with 117 events in a planned enrollment of 210 patients; secondary endpoints included overall survival (OS), objective response rate (ORR), and safety. Results: Between December 2023 and September 2024, 226 patients were randomized to each group (150 vs 76 patients). With a median follow-up of 8.5 months, PFS was significantly longer in the ONO-4578 group than the placebo group with a hazard ratio (HR) of 0.67 (90% confidence interval [CI]: 0.48–0.92; P = 0.040; median PFS: 9.0 vs 6.9 months). At a minimum follow-up of 7.4 months, OS favored the ONO-4578 group (median OS: not reached vs 12.7 months; HR: 0.60 [95% CI: 0.37–0.96]). ORR was also higher in the ONO-4578 group (62.0% vs 48.7%). The most common treatment-emergent adverse events (TEAEs) in the ONO-4578 group were diarrhea (55.7% vs 45.3%), anemia (55.0% vs 34.7%), and peripheral sensory neuropathy (50.3% vs 46.7%). Serious TEAEs occurred in 53.7% of patients in the ONO-4578 group and 42.7% in the placebo group. Conclusions: ONO-4578 combined with NIVO and chemo significantly improved PFS compared with placebo combined with NIVO and chemo in treatment-naive patients with HER2-negative unresectable adv/rec G/GEJ cancer with no new safety concerns. Clinical trial information: NCT06256328 .

TPS4242 Background: Claudin 18.2 (CLDN18.2) is a transmembrane tight junction protein with expression restricted to the gastric mucosal epithelia where CLDN18.2 protects against paracellular acid leakage and associated gastritis. 1 CLDN18.2 overexpression has been observed in several tumor types, including gastric, esophageal, and pancreatic cancer. 2,3 Loss of cell polarity in these tumors results in CLDN18.2 localization to surfaces that are more readily accessible to biologics and effector cells. This expression pattern makes CLDN18.2 a compelling target for immune-stimulating antibody conjugates (ISACs) that combine the specificity of tumor-targeting antibodies with the potency and durability of immune activation. BDC-4182 is a next-generation ISAC consisting of a CLDN18.2-targeting antibody covalently attached to a novel toll-like receptor (TLR)7/8 agonist via a non-cleavable linker. In preclinical models, systemic delivery of ISACs has been shown to broadly activate the innate and adaptive immune system, leading to complete tumor regression. A BDC-4182 surrogate induced immunologic memory and epitope spreading as evidenced by rejection of tumor cells that no longer express the target antigen (CLDN18.2) following re-challenge. 4,5 Methods: This is a first-in-human Phase 1 dose escalation and Phase 2 expansion study of BDC-4182. Up to 122 patients with advanced gastric and gastroesophageal cancer will be enrolled. To optimize tolerability, BDC-4182 is administered via an intra-patient step-up dosing regimen wherein subjects receive lower initial priming doses prior to the target dose. Primary objectives are to define safety and tolerability and to determine the recommended phase 2 dose (RP2D) of BDC-4182 as a single agent. Secondary objectives will evaluate the preliminary anti-tumor activity of BDC-4182, analyze PK characteristics of BDC-4182, and evaluate the immunogenicity of BDC-4182 as a single agent. Exploratory analyses will also be conducted to explore potential biomarkers in blood and tumor tissue associated with exposure, efficacy, or safety of BDC-4182, and to define CLDN18 expression in tumor tissue. This study is being conducted in Australia, South Korea, and Taiwan. References: 1. Suzuki K, Sentani K, Tanaka H, et al. Cell Mol Gastroenterol Hepatol. 2019;8:119-142. 2. Hong JY, An JY, Lee J, et al. Transl Cancer Res. 2020;9:3367-3374. 3. Chen J, Xu Z, Hu C, et al. Front Oncol. 2023;13:1132319.4. Fu C, Luo A, Liu J, et al. J Immunother Cancer. 2024;12(Suppl 2):Abstract 1052. 5. Kim HK, Monnier J, Fu C, et al. J Immunother Cancer. 2023;11(Suppl 1):Abstract 1147-D. Clinical trial information: NCT06921837 .

PURPOSE:EP4, a key receptor in the prostaglandin E2 axis, mediates tumor immunosuppression; the EP4 antagonist ONO-4578 plus nivolumab showed manageable safety, immune activation, and preliminary antitumor activity in previously treated gastric/gastroesophageal junction cancer (G/GEJC). This study explored whether ONO-4578 enhances the efficacy of nivolumab plus chemotherapy in unresectable advanced or recurrent G/GEJC. METHODS:This multicenter, double-blind, randomized phase II study enrolled chemotherapy-naïve patients with human epidermal growth factor receptor 2 (HER2)-negative unresectable advanced or recurrent G/GEJC. Patients were randomly assigned (2:1) to receive oral ONO-4578 or matching placebo, each in combination with nivolumab and oxaliplatin-based chemotherapy. The primary end point was investigator-assessed progression-free survival (PFS). Secondary end points included overall survival (OS), objective response rate (ORR), and safety. RESULTS:At the data cutoff, 226 patients were randomly assigned to the ONO-4578 group (n = 150) and the placebo group (n = 76). Adding ONO-4578 significantly improved PFS (hazard ratio [HR] of 0.67 [90% CI, 0.48 to 0.92]; P = .040 [prespecified two-sided α = .10]), with favorable OS at a prespecified analysis with limited follow-up (HR of 0.60 [95% CI, 0.37 to 0.96]) and ORR (62.0% v 48.7%). Exploratory subgroup analyses suggested that the ONO-4578 regimen provided greater benefit in PD-L1 combined positive score (CPS) ≥1, whereas no clear benefit was observed in those with CPS <1/indeterminate patients. In an extended follow-up exploratory OS analysis with a minimum follow-up of 16.1 months, OS numerically favored the ONO-4578 regimen. Common treatment-emergent adverse events in the ONO-4578 group were diarrhea (55.7% v 45.3%) and anemia (55.0% v 34.7%). CONCLUSION:This study demonstrated promising efficacy and acceptable safety of an ONO-4578 regimen as first-line treatment for HER2-negative unresectable advanced or recurrent G/GEJC. These findings warrant confirmation in a phase III trial.

BACKGROUND:Highly vascularised neuroendocrine tumours (NETs) are attractive targets for foslinanib (CVM-1118), which disrupts vasculogenic mimicry and induces apoptosis via tumour necrosis factor receptor-associated protein 1. We evaluated the efficacy and safety of CVM-1118 in advanced NETs. METHODS:Patients with grades 1-2, well-differentiated lung, gastrointestinal, or pancreatic NETs, refractory or intolerant to one or more standard therapies and progressing within 6 months, received CVM-1118 (200-300 mg orally twice daily) in 28-day cycles. Primary endpoint was progression-free survival (PFS); secondary endpoints included objective response rate (ORR), disease control rate (DCR), overall survival (OS), and safety. RESULTS:Of 43 enroled participants, 35 were efficacy-evaluable; most had grade 2 pancreatic (63%) or gastrointestinal (34%) NETs with two prior therapies. Median PFS was 10.5 months (95% CI, 5.6-22.3). ORR was 3%, DCR was 77%, and median OS was not reached (95% CI, 23.8-NR). Sensitivity analysis in the full analysis set (N = 43) showed a PFS estimate broadly aligned with the primary analysis (median, 8.4 months); patients with prior everolimus, sunitinib, or peptide receptor radionuclide therapy (N = 22; median, 8.3 months) showed similar findings. Treatment-related adverse events occurred in 44%, mostly grades 1-2, with no serious events. CONCLUSIONS:CVM-1118 demonstrates favourable efficacy and safety in advanced NETs. CLINICAL TRIAL REGISTRATION:ClinicalTrials.gov identifier, NCT03600233.

Adenosine deaminase acting on RNA 1 (ADAR1) contributes to immunotherapy resistance by suppressing interferon signaling. Therapeutic targeting of ADAR1 has not been achieved to date in clinical settings. Here, we discover all-trans retinoic acid (ATRA) promotes ADAR1 protein degradation in cancer. In addition, ATRA induces PD-L1 and combination of ATRA and PD-1 blockade reprograms tumor microenvironments to unleash antitumor immunity, thereby impeding tumor growth. Mechanistically, we identify USP7 as a key regulator for ADAR1 protein stability. ATRA disrupts USP7-ADAR1 interaction and promotes ADAR1 ubiquitination and degradation. ATRA leads to ADAR1 retinoylation, which results in disruption of USP7-ADAR1 complex. Our clinical data shows a positive correlation between USP7 and ADAR1 in various types of cancer. Overall, this study sheds light on control of ADAR1 protein turnover and proposes a mechanism-driven combination therapy using ATRA and PD-1/PD-L1 blockade to convert immunologically "cold" into "hot" tumors, holding potential for clinical translation.

Objective A multicenter, randomized phase II trial to compare two first-line triplet treatments for advanced pancreatic ductal adenocarcinoma (PDAC). Methods Patients with histologically confirmed advanced PDAC were randomized 1:1 to receive S-1/leucovorin plus oxaliplatin, and gemcitabine (SLOG) or modified FOLFIRINOX (mFOLFIRINOX). Tumor response was assessed every eight weeks. The primary endpoint was progression-free survival (PFS). Secondary endpoints were overall survival (OS), objective response rate (ORR), safety and biomarker studies. Results A total of 129 patients (65 SLOG, 64 mFOLFIRINOX) were enrolled. After a median follow-up of 37.7 months, no significant differences were observed between the SLOG and mFOLFIRINOX arms in median PFS (7.5 vs. 6.5 months; p = 0.88), median OS (12.9 vs. 12.1 months), or objective response rate (38.5% vs. 26.6%). HRD (homologous recombination deficiency) mutations were found in 14 of 108 profiled patients (12.9%). Patients with HRD mutations had significantly longer median PFS (11.9 vs. 7.0 months; p = 0.008) and OS (17.7 vs. 11.7 months; p = 0.036). The safety profiles differed: grade 3/4 neutropenia was significantly less common with SLOG (15.4% vs. 53.1%; p < 0.001), while SLOG had more grade 3/4 non-hematological toxicities. Conclusion SLOG did not demonstrate superiority in PFS over mFOLFIRINOX, and mFOLFIRINOX therefore remains as one of the preferred first-line standards. Given its lower incidence of severe neutropenia and its convenience with oral S-1, SLOG may warrant further investigation in selected Asian patients with advanced PDAC.

Objective:To develop a brief, clinician-administered Chinese-language Breakthrough Cancer Pain Assessment (BCPA) instrument and evaluate its content validity, inter-rater reliability, and ability to detect change in selected rescue medication-related items. Methods:The 11-item BCPA was developed from literature review, clinical input, and three Delphi rounds with 14 experts. Inter-rater reliability was evaluated through independent physician and nurse interviews with 30 participants with cancer and breakthrough cancer pain (BTcP). In an exploratory observational phase, selected BCPA responses were compared in 77 participants before and 7 days after routine-care initiation of fentanyl buccal soluble film. Results:In the third Delphi round, all items had an item-level content validity index of 1.00 and the scale-level content validity index based on universal agreement (S-CVI/UA) was 1.00. Kappa coefficients for categorical items ranged from 0.507 to 0.888, and intraclass correlation coefficient [ICC(2,1)] values for numerical items ranged from 0.836 to 0.979. The proportion reporting pain relief within 15 minutes increased from 33.8% to 66.2% (matched-pairs odds ratio, 4.57; 95% CI, 2.02-10.35; P < 0.001). Mean satisfaction with the effectiveness of rescue medication increased from 5.96 to 7.60, and perceived improvement in sleep and mood increased from 6.01 to 7.40 (both P < 0.001). Conclusions:The Chinese-language BCPA showed preliminary content validity and inter-rater reliability. Selected rescue medication-related items detected pre/post changes in an uncontrolled observational sample. Further evaluation of response processes, criterion-related validity, cross-cultural validity, and responsiveness is required before routine clinical implementation.

4042 Background: In HERIZON-GEA-01, replacing 1L trastuzumab (tras) + CT with zanidatamab + CT ± tislelizumab significantly improved progression-free survival and, with tislelizumab, yielded a statistically significant overall survival benefit in HER2+ mGEA. The safety profile was manageable; diarrhea was the most common AE. Here we further characterize GI AEs and diarrhea management. Methods: Eligible patients (pts) with previously untreated HER2+ mGEA were randomized 1:1:1 to zanidatamab (1800 mg [<70 kg]/2400 mg [≥70 kg] IV Q3W) + tislelizumab (200 mg IV Q3W) + capecitabine/oxaliplatin (CAPOX) or 5-FU/cisplatin (FP); zanidatamab + CAPOX or FP; or tras + CAPOX or FP. CT could be discontinued per physician preference after cycle 6. Tras dose reductions were not permitted. Diarrhea prophylaxis (loperamide 4 mg orally BID) was mandatory in zanidatamab-containing arms for the first 7 days of cycle 1. Results: Median treatment duration was 43.1 wk with zanidatamab + tislelizumab + CT, 31.0 with zanidatamab + CT, and 30.0 with tras + CT. Median number of CT cycles was 6, 6, and 7, respectively. Diarrhea was the most common GI AE in all arms; other GI AEs were generally similar across arms. Among pts who experienced diarrhea, most had first onset in cycle 1 (76% in ≤3 wk) with median duration <2.5 wk (Table). Few pts had their first onset of diarrhea occur after cycle 6 when pts could discontinue CT. HER2-targeted therapy discontinuations (4.1%, 1.3%, 0.3%, respectively) and dose reductions (9.9%, 10.8%, NA) or delays (13.6%, 13.4%, 7.6%) due to diarrhea were infrequent. Diarrhea was more often managed with CT dose reduction (21.8%, 23.6%, 14.2%, respectively). Immune-mediated colitis occurred in 2.7% of pts with zanidatamab + tislelizumab + CT. Additional incidence and management data will be presented. Conclusions: In zanidatamab-treated pts, most diarrhea events were grade 1/2, and first-onset events tended to occur in cycle 1 and resolved in <3 wk. Diarrhea rarely led to zanidatamab discontinuation. The safety of zanidatamab-containing regimens appears favorable given the survival benefits; diarrhea should be managed with prophylactic loperamide and CT dose modifications as needed. Clinical trial information: NCT05152147 . Diarrhea Zanidatamab + Tislelizumab + CT n = 294 Zanidatamab + CT n = 305 Tras + CTn = 302 Any-grade, n (%) 244 (83.0) 241 (79.0) a 161 (53.3) Grade 1 79 (26.9) 80 (26.2) 84 (27.8) Grade 2 92 (31.3) 99 (32.5) 38 (12.6) Grade ≥3 73 (24.8) 61 (20.0) 39 (12.9) Time to first onset, n (%), wk ≤3 188 (77.0) 192 (79.7) 108 (67.1) >3 to ≤6 25 (10.2) 27 (11.2) 22 (13.7) >6 to ≤9 7 (2.9) 14 (5.8) 11 (6.8) >9 to ≤12 4 (1.6) 4 (1.7) 2 (1.2) >12 to ≤18 8 (3.3) 3 (1.2) 7 (4.3) >18 12 (4.9) 1 (0.4) 11 (6.8) Duration of first onset, median (95% CI), wk 2.0 (1.6, 2.6) 2.4 (1.9, 2.9) 1.4 (1.0, 2.1) a Grade missing for 1 pt.