Gastric cancer remains a significant cause of cancer-related morbidity and mortality in the Asia-Pacific region, where Helicobacter pylori infection is common and national cancer screening programs are widely implemented. Eradication therapy has been shown to reduce gastric cancer risk; however, residual risk persists in individuals with established precancerous changes. In addition, screening and surveillance practices vary across countries according to epidemiological and healthcare contexts. This review summarizes current approaches to the prevention continuum strategies of H. pylori-associated gastric cancer in the Asia-Pacific region. Drawing on representative national experiences, we discuss how screening, eradication, and post-eradication surveillance have been implemented across diverse epidemiologic and healthcare settings. By integrating these complementary strategies from infection to cancer care, we highlight the rationale for different national prevention models and the remaining challenges in gastric cancer control.

Recent randomized controlled trials (RCTs) regarding the outcomes of neoadjuvant chemotherapy for patients with resectable pancreatic cancer (PC) reported inconsistent results. As the survival rate of FOLFIRINOX was found to be superior to that of gemcitabine, interest in the efficacy of neoadjuvant chemotherapy with FOLFIRINOX for resectable PC is growing. In this study, we aimed to investigate the efficacy of neoadjuvant FOLFIRINOX in patients with resectable PC. This international (South Korea, Australia, and Taiwan), multicenter, phase 3, RCT will include 609 patients with resectable pancreatic ductal adenocarcinoma and ECOG performance 0–1. Resectable PC is defined as no arterial contact and no tumour contact with the superior mesenteric vein/portal vein or ≤ 180°contact without vein contour irregularity. Neoadjuvant FOLFIRINOX consisted of oxaliplatin (85 mg/m2), administered intravenously over 2 h, followed by leucovorin (400 mg/m2) over 2 h and irinotecan (180 mg/m2) over 90 min, administered concurrently. Subsequently, an intravenous bolus infusion of 5-FU (400 mg/m2) and a continuous infusion of 5-FU (2400 mg/m2) over 46 h, repeated every 2 weeks for 6 cycles. Adjuvant therapy with modified FOLFIRINOX (mFOLFIRINOX) included oxaliplatin (85 mg/m2), irinotecan (150 mg/m2), leucovorin (400 mg/m2), and fluorouracil (2400 mg/m2) over 46 h and repeated every 2 weeks, with six cycles in the neoadjuvant group and 12 cycles in the upfront surgery group. The primary endpoint is a two-year survival rate by intention-to-treat. Secondary outcomes are overall survival, disease-free survival, resection rate, R0 resection rate, lymph node negative rate, recurrence rate, response rate. When calculating with a significance level of 5

4193 Background: Pancreatic ductal adenocarcinoma (PDAC) remains one of the most lethal malignancies with poor outcomes in advanced disease. Nesuparib is a dual tankyrase (TNKS) and poly(ADP-ribose) polymerase (PARP) inhibitor that induces a “BRCAness” phenotype via WNT and Hippo signaling. This Phase Ib study evaluated the safety, tolerability, and preliminary antitumor activity of nesuparib combined with standard first-line chemotherapy in patients with locally advanced or metastatic PDAC. Methods: This multicenter, open-label, Phase Ib dose-finding study evaluated oral nesuparib plus GemAbraxane or mFOLFIRINOX in advanced PDAC. Nesuparib was administered orally using a 3+3 dose-escalation design with intermittent schedules, including DL1 (25 mg, 5 days on/2 days off), DL-1 (12.5 mg, 5 days on/2 days off), and DL-2 (12.5 mg, 3 days on/4 days off). Primary objectives were to assess safety and determine the maximum tolerated dose and recommended Phase II dose. Secondary objectives included preliminary efficacy. Results: As of December 31, 2025, 27 patients were enrolled and treated (GemAbraxane, n = 14; mFOLFIRINOX, n = 13). Most patients had metastatic disease. In the GemAbraxane arm, acceptable tolerability was confirmed at DL-1 and DL-2, whereas tolerability was not established in the mFOLFIRINOX arm. Across both treatment arms, grade 3/4 AEs were mainly hematologic toxicities. Rates of anemia, thrombocytopenia, and neutropenia were 57.1%, 64.3%, and 92.9% in the GemAbraxane arm, compared with 84.6%, 92.3%, and 84.6% in the mFOLFIRINOX arm, respectively. No treatment-related deaths occurred, and most AEs were manageable with standard supportive measures. Non-hematologic AEs were mostly low-grade and manageable. In the GemAbraxane arm, the objective response rate (ORR) and disease control rate (DCR) were 53.8% and 92.3%, respectively, including one patient with a complete response (CR) of the target lesion and overall survival exceeding 3 years. Median progression-free survival (mPFS) was not reached, and median overall survival (mOS) was 14.2 months (data immature and follow-up is ongoing). In the mFOLFIRINOX arm, the ORR was 38.5% with a DCR of 92.3%, while mPFS and mOS were 7.33 and 18.5 months, respectively. Conclusions: Nesuparib combined with GemAbraxane demonstrated acceptable tolerability and encouraging antitumor activity in advanced PDAC. These findings support further evaluation of nesuparib using a 12.5 mg intermittent dosing schedule in the first-line treatment setting; a Phase II trial is currently ongoing. Clinical trial information: NCT05257993 . Outcome Nesuparib + GemAbraxane (n=13) Nesuparib + FOLFIRINOX(n=13) PR 7 (53.8%) 5 (38.5%) SD 5 (38.5%) 7 (53.8%) PD 1 (7.7%) 1 (7.7%) ORR 53.8% 38.5% DCR 92.3% 92.3% mOS 14.20 mo (data immature) 18.50 mo mPFS Not reached 7.33 mo

TPS3185 Background: KRAS is one of the most frequently mutated oncogenes in human cancers, with the G12C mutant isoform accounting for ~15% of all KRAS mutations. Despite their promising antitumor activity and manageable safety profile in advanced solid tumors, first-generation KRAS G12C inhibitors are often limited by acquired resistance in the monotherapy setting. MK-1084 is a next-generation, highly potent and selective KRAS G12C–GDP covalent inhibitor that exerts downstream regulation of the MAPK pathway. EGFR-mediated reactivation of RAS-MAPK signaling is proposed as a key driver of resistance to KRAS G12C inhibitors, particularly in colorectal cancer (CRC). The combination of KRAS G12C inhibitors and EGFR-targeted monoclonal antibodies has demonstrated clinical benefit in KRAS G12C-mutated CRC and non-small cell lung cancer (NSCLC), supporting the potential of this mutation as a clinically-relevant target across tumor types. KANDLELIT-014 (NCT07209111) is a phase 2, randomized, open-label, multicenter, tumor-agnostic study of MK-1084 as monotherapy and in combination with EGFR inhibitor cetuximab in participants with previously treated advanced solid tumors harboring a KRAS G12C mutation. Methods: Eligible participants are aged ≥18 years with histological or blood-based KRAS G12C-mutated locally advanced unresectable or metastatic solid tumors (other than CRC) that have progressed on or following standard-of-care systemic treatment, or for whom no satisfactory alternative treatment options are available. Additional eligibility criteria include an ECOG PS score of 0 or 1 and measurable disease per RECIST v1.1. Participants were excluded if they had uncontrolled, significant cardiovascular or cerebrovascular diseases; an additional progressive active malignancy that required treatment within the past 3 years; or active CNS metastases, carcinomatous meningitis, or primary brain tumors. Participants will be randomly assigned 1:1 to receive MK-1084 100 mg orally once daily as monotherapy (Arm 1) or in combination with cetuximab 500 mg/m 2 intravenously every 2 weeks (Arm 2) until discontinuation criteria are met. Randomization will be stratified according to the following tumor groups: NSCLC, pancreatic ductal adenocarcinoma, endometrial cancer, biliary tract cancer, and other solid tumors. The primary end points are ORR per RECIST v1.1 as assessed by blinded independent central review (BICR), safety, and tolerability. Key secondary end points include OS, DOR per RECIST v1.1 by BICR, and PFS per RECIST v1.1 by BICR. Imaging will be performed every 6 weeks until Week 18, every 8 weeks until Week 50, and every 12 weeks thereafter until disease progression or discontinuation. AEs will be evaluated from randomization to 30 days after the last dose of study treatment per NCI CTCAE v5.0. This global study is actively enrolling. Clinical trial information: NCT07209111 .

Polo-like kinase 1 (PLK1) has been emerging as a promising therapeutic target in solid tumors due to its central role in cell cycle regulation and cancer cell proliferation. In biliary tract cancer (BTC), cell cycle-related factors such as PLK1, CDKs, and Aurora kinase are frequently overexpressed or aberrantly activated, driving tumor progression. However, studies targeting these proteins in BTC remain limited. BUBR1, a critical mitotic checkpoint protein, is essential for maintaining chromosomal stability by ensuring proper chromosome alignment and segregation during cell division. This study evaluated the antitumor effects of a PLK1 inhibitor plogosertib in BTC and identified BUBR1 as a potential biomarker to predict treatment response. Total 9 BTC cell lines (SNU-245, SNU-308, SNU-478, SNU-869, SNU-1196, HuCCT-1, TFK-1, SNU-2670, SNU-2773) were used. We used plogosertib (PLK1 inhibitor), ceralasertib (ATR inhibitor) and panobinostat (HDAC2/3 inhibitor). The anticancer effects of plogosertib, both alone and in combination with ceralasertib and panobinostat, were evaluated through MTT assay, Colony formation assay, Annexin-V assay, and Cell cycle analysis. The effect of plogosertib on mitotic arrest was assessed using phospho-histone H3 assay and Immunofluorescence. Plogosertib monotherapy showed higher anticancer effects in BUBR1-high BTC cells (SNU2773, SNU478) compared to BUBR1-low cells (SNU869, SNU245). Plogosertib promoted mitotic checkpoint complex (MCC) formation in prometaphase, arresting mitosis and ultimately leading BTC cells to undergo apoptosis. However, plogosertib also induced ATR activation, which may limit its efficacy by initiating DNA repair pathways. ATR inhibition by ceralasertib further enhanced the anticancer effects of plogosertib in BUBR1-high cells. In BUBR1-low cells, plogosertib reduced BUBR1 protein expression, possibly through ubiquitination-proteasome-mediated degradation, limiting MCC formation and its therapeutic effects. Among several candidates regulating ubiquitination processes, HDAC2/3 inhibition by panobinostat enhanced the responsiveness of BUBR1-low cells to plogosertib. BTC cells with high BUBR1 expression are sensitive to the PLK1 inhibitor plogosertib, which shows synergistic effects when combined with an ATR inhibitor. In contrast, BTC cells with low BUBR1 expression which are relatively insensitive to plogosertib, HDAC2/3 inhibition increases the sensitivity to plogosertib. These findings suggest that targeting PLK1 could be an effective strategy for BTC treatment, especially with BUBR1 expression as a potential biomarker to inform optimal combination therapies. Yoojin Jeong, Ah-Rong Nam, Kyoung-Seok Oh, Jae-Min Kim, Ju-Hee Bang, Sea Young Choo, Hyo Jung Kim, Jeesun Yoon, Tae-Yong Kim, Do-Youn Oh. Evaluation of antitumor effects of plogosertib, PLK1 inhibitor in biliary tract cancer with BUBR1 as a potential biomarker [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 5406.

BACKGROUND:Trastuzumab resistance in HER2-positive cancers remains a significant clinical challenge with limited therapeutic options. Although the tumor-promoting role of the Yes-associated protein (YAP) pathway is well established, its role in trastuzumab resistance remains unclear. METHODS:We established four trastuzumab-resistant (HR) cell lines (NCI-N87HR, SNU216HR, SNU2670HR, and SNU2773HR) from HER2-positive gastric cancer and biliary tract cancer cell lines. YAP pathway activation was assessed using Phospho-RTK arrays, bulk RNA-Seq, and immunofluorescence. Antitumor effects of YAP targeting were evaluated with MTT assays, cell-cycle analysis, migration assays, RT-qPCR, ELISA, and xenograft models of SNU-2773 and SNU-2773HR cells. Immune modulation by YAP was studied through co-culture experiments with human PBMCs and cancer cells, followed by flow cytometry analysis of immune markers. RESULTS:Upregulation and activation of the YAP/TAZ pathway were observed in HR cells, indicated by elevated ROR2 levels and nuclear translocation of YAP. This activation, driven by YAP/TEAD-dependent Wnt5a expression, suggests a positive-feedback mechanism that amplifies YAP activity. Elevated YAP and TEAD levels were observed in patient tumor tissues during disease progression following HER2-targeted therapies. Targeting YAP disrupted its oncogenic effects and restored sensitivity to trastuzumab, increased activation of CD4+ and CD8+ T cells in PBMCs, likely via PD-L1 downregulation and enhanced immunogenic cell death. Verteporfin, a YAP-TEAD inhibitor, effectively reduced tumor growth and increased apoptosis in mouse models bearing HR tumors. CONCLUSIONS:Targeting the ROR2-YAP/TEAD axis presents a promising therapeutic approach to overcome trastuzumab resistance in HER2-positive cancers, offering a potential strategy for enhancing treatment efficacy and improving clinical outcomes.

BACKGROUND:Targeting CDKs has emerged as a significant strategy in cancer drug development. While CDK4/6 inhibitors have proven effective in several cancers, CDK2 and CDK9 inhibitors are under clinical trials. In biliary tract cancer (BTC), CDK2 and CDK9 expression levels are elevated compared to normal tissue. CDK9, a transcriptional CDK, regulates RNAPII, promoting the transcription of oncogenes, such as MCL1. Aberrant CDK activation contributes to cancer progression and apoptosis evasion in BTC. Notably, MCL1 is frequently amplified in intrahepatic cholangiocarcinoma (16-21%), supporting the therapeutic potential of CDK2 and CDK9. However, targeting CDK2/9 in BTC has not yet been explored. This study aimed to evaluate CDK2/9 inhibition and develop possible biomarker strategies in BTC. METHODS:Nine BTC cell lines (SNU245, SNU308, SNU478, SNU869, SNU1196, SNU2670, SNU2773, TFK1, and HUCCT1) were used. Fadraciclib (CDK2/9 inhibitor), olaparib (PARP inhibitor), and JQ1 (BRD4 inhibitor) were used. Anti-cancer effects were evaluated using MTT assay, colony formation assay, annexin-V assay, and cell cycle analysis. HR-mediated DNA damage repair was assessed using foci formation assay and DRGFP assay. Combination therapies were evaluated in vitro and in vivo. RESULTS:Fadraciclib was more effective in MCL1-High cells, reducing RNAPII phosphorylation and MCL1. Fadraciclib also inhibited HR gene transcription. Fadraciclib-olaparib combination showed synergy in MCL1-High cells and xenograft models. Conversely, in MCL1-Low cells, Fadraciclib upregulated BRD4, restoring RNAP II activity and oncogenes transcription. Combination of fadraciclib-JQ1 suppressed this restoration and showed synergy in vitro and in vivo. CONCLUSIONS:MCL1-High BTCs are sensitive to CDK2/9 inhibition and benefit from combination with PARP inhibitor. In MCL1-Low BTCs, combining CDK2/9 inhibitor and BRD4 inhibitor may represent an optimal strategy for new drug development.

PARP inhibitors have demonstrated antitumor efficacy in solid tumors, including pancreatic ductal adenocarcinoma (PDAC) characterized by homologous recombination deficiency (HRD). The definition of HRD and other potential biomarkers should be further evaluated using PARP inhibitors. JPI-547 is a novel dual inhibitor targeting PARP1/2 and Tankyrase1/2. Herein, we demonstrate the potent antitumor activity of JPI-547 against BRCA2-/- PDAC cells. JPI-547 outperformed most PARP inhibitors, with a half-maximal inhibitory concentration approximately 10-fold lower than that of olaparib. JPI-547 efficiently trapped PARP1 on the chromatin, disrupted poly-ADP-ribosylation, induced G2/M phase arrest, and triggered apoptosis in PDAC cells. In addition to HRD, we identified Wnt addiction as a predictive factor for JPI-547 activity. PDAC cells reliant on Wnt signaling due to pathogenic RNF43 mutations showed increased susceptibility to JPI-547 without altering homologous recombination repair efficiency. JPI-547 disrupts the Wnt/β-catenin pathway in RNF43-mutated cells and inhibits the oncogenic YAP pathway, highlighting its multifaceted therapeutic potential in PDAC with HRD or Wnt-addiction.

Pancreatic ductal adenocarcinoma (PDAC) is characterized by poor prognosis and resistance to conventional therapies, necessitating novel treatments. The high proliferative rate and protein synthesis in PDAC induce endoplasmic reticulum (ER) stress, with Glucose-Regulated Protein 78 (GRP78), a key regulator of ER stress and the Unfolded Protein Response (UPR), playing a pivotal role in PDAC progression. Despite its relevance, GRP78-targeted therapies remain unexplored in PDAC. BOLD-100, a novel GRP78 inhibitor, presents a potential therapeutic approach by disrupting GRP78 transcription, though its effects on PDAC have yet to be fully elucidated. Here, we found that BOLD-100 induces PDAC cell death through the UPR pathway activation, leading to CHOP-dependent apoptosis. BOLD-100 generates reactive oxygen species (ROS), inducing R-loop formation that triggers a DNA damage response via the ATR/Chk1 axis. BOLD-100 synergizes with AZD6738, an ATR inhibitor, to enhance anti-tumor efficacy compared to either agent alone in both in vitro and in vivo models. These findings suggest that BOLD-100, especially in combination with an ATR inhibitor, represents a promising therapeutic option for patients with PDAC.

Targeting endoplasmic reticulum (ER) stress is emerging as a potential therapeutic strategy for developing therapies against solid tumors. GRP78, also known as the master regulator of unfolded protein response (UPR), is an anti-apoptotic ER chaperone that adjusts protein folding capacity to restore ER homeostasis. Moreover, GRP78 is an inhibitory PERK-binding protein that regulates the activation of death-triggering UPR pathways to avoid cell apoptosis. In gastric cancer (GC), GRP78 expression is elevated compared to normal tissue making GRP78 an attractive therapeutic target in GC. However, there have been limited studies on targeting GRP78 in GC. This study investigates the antitumor effects of GRP78 inhibition with BOLD-100 and explore potential biomarkers for therapeutic response in GC. A total of 9 gastric cancer cell lines (KATO-III, SNU-601, NCI-N87, MKN-45, SNU-216, SNU-719, SNU-668, AGS, SNU-638) were used. BOLD-100 (GRP78 inhibitor), TUDCA (Tauroursodeoxycholic acid; ER stress inhibitor), and AZD6738 (ATR inhibitor) were used. MTT assay, RT-qPCR, western blot, cell cycle analysis, DCF-DA staining, immunofluorescence, and Annexin V assay were performed to evaluate the antitumor effects of BOLD-100. To evaluate the effect of PERK expression level on the efficacy of BOLD-100, siRNA was used to downregulate PERK and consequent BOLD-100 effects were analyzed by MTT assay, western blot, and flow cytometry. The antitumor effect of BOLD-100 positively correlated with PERK expression. BOLD-100 suppressed the mRNA level of GRP78 leading to a subsequent increase in unfolded protein load and ROS level in a PERK expression-dependent manner. In PERK-high GC cells (KATO-III, SNU-601), BOLD-100 exerted pronounced activation of PERK-eIF2a-CHOP pathway, resulting in inhibited tumor cell growth and induced apoptosis. PERK knockdown reversed BOLD-100 induced ROS accumulation and UPR activation suggesting that PERK expression level regulates sensitivity to BOLD-100. Conversely, in PERK-low GC cells (AGS, SNU-638), BOLD-100 exerted minimal effects on UPR pathway. Rather, it induced R-loop accumulation and upregulated active forms of ATR and Chk1 - effects not observed in PERK-high cells - suggesting activation of DNA damage repair pathway. A combination of BOLD-100 and AZD6738 showed synergistic effects in PERK-low GC cells by suppressing BOLD-100 induced ATR phosphorylation. The expression of PERK determines sensitivity to GRP78 inhibition by BOLD-100 in GC. PERK-high GC cells are sensitive to BOLD-100 and show efficacy as monotherapy. In PERK-low GC cells, the combination of BOLD-100 and ATR inhibitor is an optimal therapeutic option for GC treatment. Sea Young Choo, Ah-Rong Nam, Kyoung-Seok Oh, Jae-Min Kim, Ju-Hee Bang, Yoojin Jeong, Hyo Jung Kim, Jeesun Yoon, Tae-Yong Kim, Do-Youn Oh. PERK as a biomarker to optimize therapy of GRP78 inhibitor, BOLD-100, in gastric cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 1497.

BACKGROUND & AIMS:Immune checkpoint inhibitors (ICIs) combined with cytotoxic chemotherapy are now the standard first-line treatment for advanced biliary tract cancer (BTC). With this evolving landscape, therapeutic options using ICIs after first-line failure are urgently needed. Anti-angiogenic agents may enhance anti-tumor immunity by increasing tumor antigen presentation and promoting lymphocyte infiltration and migration. We aimed to evaluate the efficacy of sitravatinib plus tislelizumab as second-line therapy for advanced BTC. METHODS:In this open-label, single-arm, phase II trial, patients were enrolled regardless of prior ICI treatment history. The primary endpoint was disease control rate. Key secondary endpoints included objective response rate, progression-free survival, overall survival, safety, and biomarker analyses (NCT04727996). RESULTS:A total of 43 patients were enrolled. The median follow-up was 10.5 months (95% CI 7.03-15.6). Nine patients had previously received ICI therapy. The disease control rate was 65.1% (95% CI 50.3-78.0), and the objective response rate was 18.6% (95% CI 9.2-32.1). Median progression-free and overall survival were 4.93 months (95% CI 3.10-8.87) and 10.3 months (95% CI 6.67-18.2), respectively. Anti-tumor activity was observed regardless of prior ICI exposure. The most common treatment-related adverse events were associated with sitravatinib and were predominantly grade 1-2. In exploratory analyses, patients with homologous recombination deficiency (HRD), detected by baseline tissue next-generation sequencing (frequency 18.5%), showed better outcomes than those without HRD. Responders displayed higher inflammatory signaling in baseline and on-treatment tumor tissue compared with non-responders. CONCLUSIONS:Sitravatinib plus tislelizumab demonstrated meaningful efficacy and an acceptable safety profile as second-line therapy for advanced BTC. HRD-based patient selection may provide a promising strategy for optimizing treatment in this setting. CLINICALTRIALS: GOV IDENTIFIER:NCT04727996 IMPACT AND IMPLICATIONS: The results of this multi-center, open-label, phase II study suggest that immunotherapy and anti-angiogenic agent combination treatment has a promising efficacy and safety as second-line treatment for patients with advanced biliary tract cancer. Furthermore, the presence of homologous recombination deficiency detected on tumor next-generation sequencing may select patients who have benefit from this combination, which supports further research exploring immunotherapy with anti-angiogenics combination strategy in this setting. CLINICALTRIALS:gov Identifier NCT04727996.

TPS4227 Background: Pancreatic ductal adenocarcinoma (PDAC) is a leading cause of cancer deaths, with most cases diagnosed at advanced stages. Current maintenance therapy with the PARP inhibitor, olaparib, benefits only patients with germline BRCA1/2 mutations (Approximately 5-7 % of PDAC cases). However, homologous recombination deficiency (HRD)-related mutations occur in ~15% of PDACs, potentially expanding the utility of PARP inhibitors. Nesuparib, a next-generation PARP inhibitor, also targets tankyrase, disrupting WNT and Hippo signaling pathways which are critical for homologous recombination repair. This dual mechanism mimics BRCA loss ("BRCAness"), sensitizing HRD-positive tumors without BRCA mutations to PARP inhibition, broadening therapeutic options. Combining PARP inhibitors with chemotherapy (e.g., irinotecan or platinum-based drugs) enhances sensitivity to DNA damage. Preclinical studies showed nesuparib inhibited tumor growth as monotherapy and achieved higher efficacy in combination with standard treatments. In a prior phase I trial, nesuparib showed promising antitumor activity, with overall response rate of 28.2% and disease control rate of 64.1%. This Phase Ib study aims to evaluate the efficacy of nesuparib in combination with standard chemotherapy for advanced PDAC using a 3+3 dose-escalation design. Methods: This multicenter, open-label, Phase Ib, dose-finding study will enroll 24–48 patients with locally advanced or metastatic PDAC. Two arms are included: Arm A (mFOLFIRINOX combination) and Arm B (GemAbraxane combination), each with 12–24 subjects across four dose groups (3–6 patients per group). Nesuparib is administered orally under fasting conditions ranging from Dose Levels -2 (12.5 mg qd) to 4 (100 mg qd), starting at Dose Level 1 (25 mg qd) with a 5 days on/2 days off schedule. Based on the occurrence of dose-limiting toxicities (DLTs), the dose may be escalated to higher levels (Dose Levels 2, 3, or 4) or reduced to lower levels (Dose Levels -1 or -2) with a 5 days on/2 days off or 3 days on/4 days off schedule. Arm A includes mFOLFIRINOX chemotherapy with biweekly oxaliplatin (65 mg/m²), leucovorin (400 mg/m²), irinotecan (135 mg/m²), and 5-FU (2,400 mg/m²). Arm B involves gemcitabine (1,000 mg/m²) and nab-paclitaxel (125 mg/m²) on Days 1, 8, and 15 of a 28-day cycle. Primary objectives are to determine the maximum tolerable dose (MTD) and recommended Phase II dose (RP2D) and to identify the optimal combination regimen based on safety. Secondary objectives include evaluating safety and antitumor activity. Enrollment began in Q1 2022. ClinicalTrials.gov ID: NCT05257993. Clinical trial information: NCT05257993 .

The receptor tyrosine-kinase HER2 (also known as ErbB2) is a well-established therapeutic target in patients with breast or gastric cancer selected on the basis of HER2 overexpression on immunohistochemistry and/or ERBB2 amplification on in situ hybridization. With advances in cancer molecular profiling and increased implementation of precision medicine approaches into oncology practice, actionable HER2 alterations in solid tumours have expanded to include ERBB2 mutations in addition to traditional HER2 overexpression and ERBB2 amplification. These various HER2 alterations can be found in solid tumour types beyond breast and gastric cancer, although few HER2-targeted therapeutic options have been established for the other tumour types. Nevertheless, during the 5 years since our previous Review on this topic was published in this journal, obvious and fruitful progress in the development of HER2-targeted therapies has been made, including new disease indications, innovative drugs with diverse mechanisms of action and novel frameworks for approval by regulatory authorities. These advances have culminated in the recent histology-agnostic approval of the anti-HER2 antibody-drug conjugate trastuzumab deruxtecan for patients with HER2-overexpressing solid tumours. In this new Review, we provide an update on the current development landscape of HER2-targeted therapies beyond breast cancer, as well as anticipated future HER2-directed treatment strategies to overcome resistance and thereby improve efficacy and patient outcomes. Anti-HER2 therapy has revolutionized the treatment of HER2-positive breast cancer. However, HER2 has emerged as a driver of various other cancers and the indications for HER2-targeted therapy have expanded to include diverse HER2-overexpressing as well as HER2-mutant tumour types beyond breast cancer, facilitated by the advent of novel agents with greater potency and distinct mechanisms of action. Some of these agents have demonstrated promising activity even against HER2-low cancers. Herein, Yoon and Oh describe the landscape of HER2 alterations and HER2-targeted drug development beyond breast cancer. They also discuss new insights into mechanisms of resistance and potential strategies by which they might be overcome. Over the past few years, the indications for HER2-targeted therapy have expanded beyond breast cancer and gastric or gastroesophageal junction cancer (G/GEJC) to include various other solid tumour types.The anti-HER2 antibody-drug conjugate trastuzumab deruxtecan has become a new standard of care for patients with treatment-refractory HER2-positive G/GEJC, HER2-mutant non-small-cell lung cancer or any HER2-overexpressing (immunohistochemistry 3+) solid tumour, owing to its potent antitumour activity and impressive clinical efficacy.Ten years after the ToGA study established the anti-HER2 antibody trastuzumab in combination with chemotherapy as the standard of care for patients with previously untreated advanced-stage HER2-positive G/GEJC, the addition of an immune-checkpoint inhibitor (the anti-PD-1 antibody pembrolizumab) to this regimen has presented a new first-line treatment option for this disease.Several potential mechanisms of resistance to HER2-targeted therapies have been identified, such as alterations that impaired drug binding to HER2 or that constitutively activate signalling pathways downstream of or parallel to HER2.Novel agents targeting HER2 and new combinations HER2-target therapies with various agents, including inhibitors of other receptor tyrosine kinases, immunotherapies and DNA damage repair inhibitors, are under investigation in clinical trials.

Abstract Background: Targeting endoplasmic reticulum (ER) stress is a potential therapeutic strategy in preclinical models of pancreatic duct adenocarcinoma (PDAC). GRP78 is known as the master regulator of the unfolded protein response (UPR) pathway, regulating ER stress by activating the UPR pathway to avoid cell apoptosis and regulates the activation of UPR pathway signals by binding PERK. Overexpression of GRP78 in PDAC results in the retention of misfolded and unassembled proteins, as well as the accumulation of ROS, leading to the promotion of genomic instability. However, there has been limited research on targeting GRP78 as a therapeutic strategy in PDAC. In this study, we aimed to investigate the anticancer effects of BOLD-100, an inhibitor of GRP78, in PDAC. Methods: We used 9 PDAC cell lines (Capan-1, AsPC-1, HPAFII, MIA-PaCa2, Panc-1, Capan-2, SNU-213, SNU-324, SNU-2918). The mouse xenograft model of Capan-1 was established for in vivo study. BOLD-100 (GRP78 inhibitor), AZD6738 (ATR inhibitor), NAC (N-Acetylcysteine; ROS scavenger) and TUDCA (Tauroursodeoxycholic acid; ER stress inhibitor) were used. MTT assay, CFA assay, cell cycle analysis, RT-PCR, western blot, immunoprecipitation, DCF-DA staining and Annexin V assay were used to elucidate the action of BOLD-100. The combination of BOLD-100 with AZD6738 has been evaluated in both in vitro and in vivo model. Results: BOLD-100 suppressed the proliferation of PDAC cells and decreased the mRNA level of GRP78, which in turn disrupted the interaction between GRP78 and PERK. BOLD-100 increased ER stress and ROS, leading to activation of PERK, eIF2a, and CHOP. Activation of UPR pathway induced CHOP-dependent apoptosis and inhibited PDAC cell growth. Moreover, TUDCA reversed the ROS accumulation induced by BOLD-100, confirming that ER stress regulates ROS levels. The accumulation of ROS upregulated the active forms of ATR and CHK1, suggesting the activation of the DNA damage repair pathway. Notably, the treatment of NAC abrogated the activation of ATR-CHK1 axis by BOLD-100-induced ROS accumulation. AZD6738 synergized with BOLD-100 in in vitro and in vivo, by suppressing BOLD-100-induced ATR phosphorylation. Conclusion: GRP78 could serve as one of the potential therapeutic targets in PDAC. The combination of BOLD-100 and AZD6738 demonstrates a synergistic effect suggesting GRP78/ATR dual targeting as a promising therapeutic option for patients with PDAC. Citation Format: Su In Lee, Ah-Rong Nam, Kyoung-Seok Oh, Jae-Min Kim, Ju-Hee Bang, Yoojin Jeong, Sea Young Choo, Hyo Jung Kim, Jeesun Yoon, Tae-Yong Kim, Do-Youn Oh. Co-downregulation of GRP78 and ATR enhances apoptosis in pancreatic ductal adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 380.

3134 Background: Neratinib, an irreversible pan-HER tyrosine kinase inhibitor, has single agent clinical activity in HER2 mutated cancer. This open-label single arm phase 2 trial investigated the efficacy and safety of the dual anti-HER2 therapy, neratinib plus trastuzumab in heavily pretreated patients with HER2 mutated solid tumors excluding HER2 amplifications. Methods: Neratinib was administered 240mg p.o. daily with trastuzumab biosimilar (Herzuma) every 3 weeks. The primary endpoint was objective response rate (ORR) by RECIST v1.1. Secondary endpoints were duration of response (DoR), progression free survival (PFS), and safety. An exploratory biomarker study was also conducted. Results: Forty patients were enrolled with a median follow-up of 11.08 months (range, 0.39-21.63 months) and a median of 3 (range 1-9) lines of prior systemic therapy. Tumor types included lung (42.5%), colorectal (20%) biliary (12.5%), and breast (7.5%). Sixty percent (60%) of patients (n=24) had HER2 mutation in the kinase domain. Among evaluable patients (n=39), the ORR was 23.1% (CR=0, PR=9) with a median DoR of 11.18 months (95% CI 0-22.63). Median PFS was 3.42 months (95% CI 1.57-5.27) and median overall survival was 9.47 months (95% CI 2.93-16.01). Grade ≥3 adverse events (AEs) occurred in 47.5% of patients (n=19) and diarrhea was the most frequently reported AE (n=10; 25%) followed by bilirubin elevation (n=2; 5%), and anemia (n=2; 5%). Conclusions: In heavily pretreated patients with HER2 mutated solid tumors, neratinib plus trastuzumab showed a moderate response rate, with a durable duration of response. Most AEs were manageable, highlighting the need for prophylactic diarrhea management. Exploratory biomarker results will be presented at the upcoming meeting. Clinical trial information: NCT06083662 .

380 Background: Tumors with homologous recombination deficiency (HRD), including BRCA and ATM mutations, have shown to predict response to poly (adenosine diphosphate [ADP]–ribose) polymerase (PARP) inhibitors. The associations between treatment efficacy of PARP inhibitor-based regimen and mutations in BRCA (BRCAm) or ATM gene (ATMm) are not well known in previously treated advanced gastric cancer (GC). Combining PARP inhibitor and irinotecan is known to synergize cytotoxicity. The aim of this analysis was to evaluate the association of HRD and efficacy of irinotecan and venadaparib combined, in patients with metastatic GC who had failed at least 2 lines of therapy. Methods: MTT assays were performed in vitro to verify and characterize synergism between venadaparib and SN-38. Data were analyzed using the GraphPad Prism (version 9.5.1) and CompuSyn (version 1.0) software. Patients with at least two prior palliative treatments were enrolled in a multi-national phase Ib trial (NCT04725994). Tumor response was evaluated according to RECIST 1.1. Exploratory genomic analysis was included to assess the correlation between efficacy and HRD. Genomic analysis was conducted using ctDNA (GuardantOMNI Gene Panel version 1.0, Redwood City, CA) on Day 1 pre-dose. Results: In MTT assays, the combination of SN-38 and venadaparib exerted synergistic effect with combination indices (CI) ranging from 0.013 to 0.991 in SNU-638 (BRCA2m), SNU-668 (BRCA1m), AGS (low ATM) and SNU-484 (HR proficient) cells. We observe the synergistic effect between SN-38 and venadaparib remained consistent even at low concentrations of venadaparib (SN-38 IC50; without venadaparib → with 10 nM of venadaparib; SNU-638(1.72→0.28), SNU-668(10.7→1.5), AGS (0.62→0.049), SNU-484(2.25->0.38)). In the dose-finding part of the clinical study, 26 patients were enrolled, 13 had received two prior treatments and 13 had received three prior treatments. At data cut-off, median duration of follow-up (range) was 4.4 (1.3 – 23.7) months. Of the 26 patients enrolled, 5 (1 BRCA2m and 4 ATMm) had HRD (19.2%) and were treated with varying doses of irinotecan and venadaparib. In the five patients with HRD, an objective response rate (ORR) was 60% and median progression-free survival (mPFS) (95% CI) was not reached (1.2–21.5). Of the 26 patients enrolled, 11 received varying doses of venadaparib plus 100 mg/m 2 of irinotecan, with an ORR of 36.4% and mPFS (95% CI) of 5.6 (3.5–not reached) months. Conclusions: Venadaparib in combination with irinotecan showed synergistic effect in vitro assays and promising clinical efficacy in the systemic treatment of refractory GC, particularly in patients with HRD. The dose expansion phase of the study is ongoing to investigate the optimal biological dose and patient selection strategies, in a randomized design. Clinical trial information: NCT04725994 .

4018 Background: In first line of advanced biliary tract cancer (BTC), immune-checkpoint inhibitor (ICI) in combination with cytotoxic chemotherapy is now standard of care supported by TOPAZ-1 and KN-966 studies. With this landscape, new drug development using ICI in second or later line setting is urgent unmet medical needs area. Anti-angiogenic agent induced improved anti-tumor immune responses by increasing tumor antigen presentation and promoting lymphocyte infiltration and migration. Methods: This study is an open-label, phase 2 trial to investigate the efficacy of sitravatinib and tislelizumab (PD1 inhibitor) combination treatment for 2L advanced BTC. Patients who received prior ICI could be enrolled. All patients received sitravatinib 120mg orally once daily in combination with tislelizumab 200mg intravenously once every 3 weeks until disease progression, unacceptable toxicity. The primary endpoint was disease control rate (DCR), with key secondary endpoints including overall response rate (ORR), progression-free survival (PFS), overall survival (OS), and safety. Tissue biopsies were conducted three times in total: screening, the first response evaluation, and disease progression. Blood samples were collected every cycles. (NCT04727996) Results: A total of 43 patients were enrolled. Data-cut off was on July 31, 2023. Median follow-up was 10.5months (95% Confidence interval (CI), 7.03-15.6). 9 patients had received prior ICI. This study met primary endpoint as a DCR of 65.1% in all population. ORR was 20.5% in unselected per-protocol population, and PFS was 4.93 months (95% CI, 3.10-8.87). OS was 10.3months (95% CI, 6.67-18.2). Similar efficacy was observed regardless of prior ICI exposure. The most common treatment-related adverse events (AEs) were sitravatinib-related; hand-foot syndrome (any grade 60.5%, grade 3/4 0%), hypertension (any grade 34.9%, grade 3/4 11.6%). Immune-related AEs (irAEs) were 46.5%, with most irAEs being grade 1-2. In exploratory analysis, patients with homologous recombination deficiency (HRD) detected by baseline tissue NGS (frequency 18.5%) showed higher ORR (60% vs 13.6%), longer PFS (not reached vs 4.87 months) and OS (21.1 vs 8.57 months) than patients without HRD. HRD detected by circulating tumor DNA had a complementary role for patient selection. RNA sequencing showed upregulation in inflammatory signal and downregulation in angiogenesis signal between screening and on-treatment tumor tissue. Responders showed higher inflammatory signaling at baseline and on-treatment tumor tissue compared to non-responders. Conclusions: Sitravatinib/tiselizumab combination as 2L therapy in patients with advanced BTC demonstrated meaningful efficacy and an acceptable safety profile. Especially, patient selection using HRD biomarker might be a promising strategy in this setting. Clinical trial information: NCT04727996 .

Background: KRAS, TP53, CDKN2A, and SMAD4 have been the main driver mutations in pancreatic ductal adenocarcinoma (PDAC). Studies on the clinical significance and treatment response to 5-fluorouracil, leucovorin, irinotecan, and oxaliplatin (FOLFIRINOX) regimen in terms of the presence of these mutations remain inconclusive. Objectives: This study aimed to compare the survival outcome and response to FOLFIRINOX chemotherapy based on the presence of four driver mutation genes. Design: A multi-center retrospective study conducted at two tertiary medical centers. Methods: This study analyzed PDAC patients who were treated with FOLFIRINOX chemotherapy as the initial treatment. Tumor specimens were analyzed by a targeted next-generation sequencing platform at two tertiary referral hospitals from January 2016 to March 2022. Patients’ demographics, survival outcomes, and chemotherapeutic response were investigated and compared according to the presence of driver mutations. Results: The analysis included 100 patients. KRAS mutation was identified in 92 (92.0%) patients, followed by TP53, CDKN2A, and SMAD4 in 63 (63.0%), 18 (18.0%), and 17 (17.0%) patients, respectively. The TP53 wild-type group demonstrated longer overall survival (OS) than the TP53 mutated group (median OS: 29 vs 19 months, p = 0.03), and TP53 served as a prognostic factor for survival (hazard ratio = 1.74, 95% confidence interval: 1.00–3.00, p = 0.048). The difference in OS according to TP53 mutation was intensified in localized pancreatic adenocarcinoma (37 vs 19 months, p = 0.01). The TP53 wild-type group demonstrated a higher objective response rate to FOLFIRINOX chemotherapy than the TP53 mutation group in localized pancreatic adenocarcinoma (50.0% vs 17.6%, p = 0.024). Conclusion: PDAC patients with wild-type TP53 demonstrated longer OS than those with TP53 mutation, and this trend was intensified in patients with localized disease. This result may be due to an impaired response to FOLFIRINOX chemotherapy in patients with TP53 mutation.

Although the efficacy of trastuzumab deruxtecan (T-DXd) against HER2-positive gastric cancers (GCs) has driven its clinical application, the precise mechanisms governing its immunomodulatory role remain unclear. In this study, we examined the immune-related mechanisms of action of T-DXd in GC cells. T-DXd exhibited potent antitumor effects in GC cells across diverse HER2 expression levels by inducing DNA damage and apoptosis. Activation of the DNA damage response by T-DXd led to increased PD-L1 expression. RNA-Seq analysis revealed that T-DXd modulated immune-related pathways, resulting in the upregulation of genes associated with inflammation and IFN signaling. Importantly, T-DXd activated the cGAS-STING pathway, inducing an IFN-I response in HER2-positive GC cells. Furthermore, T-DXd activated dendritic cells via the cancer cell-intrinsic cGAS-STING-IFN axis and enhanced PBMC-mediated tumor cell killing by activating CD8+ T cells. These findings provide valuable insights into the role of the cytosolic DNA sensing pathway in the action of T-DXd and offer a compelling rationale for combining T-DXd with immune checkpoint blockade therapies in GC treatment.

Abstract Background: Targeting CDKs has emerged as a significant strategy in the development of new drugs. The CDK4/6 inhibitors have proven their efficacy in several tumor types, while the CDK2 and CDK9 inhibitors are currently undergoing clinical trials. In biliary tract cancer (BTC), gene expressions of CDK2 and CDK9 are elevated compared to normal tissue. CDK9, a transcriptional CDK, regulates RNA polymerase II (RNAP II), leading to enhanced transcription of oncogenes, such as MCL1. Aberrant activation of these CDKs is associated with cancer progression and evading apoptosis in BTC. Notably, MCL1 is frequently amplified in intrahepatic cholangiocarcinoma (16-21%). This finding underscores the potential significance of CDK2 and CDK9 as therapeutic targets in BTC. However, in BTC, targeting CDK2 or CDK9 has not yet been studied. In this study, we aimed to test CDK2/9 targeting and develop possible biomarker strategies in BTC. Method: A total 9 BTC cell lines (SNU245, SNU308, SNU478, SNU869, SNU1196, SNU2670, SNU2773, TFK1, and HUCCT1) were used. Fadraciclib (CDK2/9 dual inhibitor), Olaparib (PARP inhibitor), JQ1 (BRD4 inhibitor) was used. MTT assay, Colony formation assay, Annexin-V assay, and Cell cycle analysis were performed for evaluation of anti-cancer effects. The effect of Fadraciclib on homologous recombination (HR)-mediated DNA damage repair was assessed using focus formation assay and DRGFP assay. Combination of Fadraciclib with Olaparib or JQ1 was evaluated in vitro and in vivo. Result: The anti-tumor effect of Fadraciclib monotherapy was relatively higher in MCL1-High BTC cells (SNU869, SNU2773) compared to MCL-Low cells (SNU245, SNU2670). In MCL1-High cells, Fadraciclib inhibited CDK9, leading to downregulation of RNAP II phosphorylation at Serine 2 and MCL1. Fadraciclib also interfered with HR-mediated DNA damage response by inhibiting transcription of HR-related genes. The combination of Fadraciclib and Olaparib exhibited synergistic anti-tumor effects in vitro in MCL1-High cells and in vivo xenograft model. Conversely, in MCL1-Low cells, Fadraciclib increased BRD4 mRNA expression, leading to the restoration of CDK9-RNAP II activity. This reactivation of RNAP II restored cellular transcription homeostasis, thereby reactivating the transcription of oncogenes such as MCL1. Combination of Fadraciclib and JQ1 showed synergistic effects in vitro in MCL1-Low cells and in vivo xenograft model by inhibiting restored CDK9-RNAP II activity. Conclusion: MCL1-High BTC cells are sensitive to CDK2/9 inhibitor and show synergism between CDK2/9 inhibitor and PARP inhibitor. In MCL1-Low BTC, a combination of a CDK2/9 inhibitor and a BRD4 inhibitor might represent an optimal strategy for new drug development. Citation Format: Jae-Min Kim, Ah-Rong Nam, Kyoung-Seok Oh, Ju-Hee Bang, Yoojin Jeong, Sea Young Choo, Su In Lee, Hyo Jung Kim, Jeesun Yoon, Tae-Yong Kim, Do-Youn Oh. Anti-tumor effects of fadraciclib, CDK2/9 inhibitor, in biliary tract cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5711.