The European Society for Medical Oncology (ESMO) Clinical Practice Guidelines for the diagnosis, treatment and follow-up of patients with gastric cancer (GC), published in late 2022 and the updated ESMO Gastric Cancer Living Guideline published in July 2023, were adapted in August 2023, according to previously established standard methodology, to produce the Pan-Asian adapted (PAGA) ESMO consensus guidelines for the management of Asian patients with GC. The adapted guidelines presented in this manuscript represent the consensus opinions reached by a panel of Asian experts in the treatment of patients with GC representing the oncological societies of China (CSCO), Indonesia (ISHMO), India (ISMPO), Japan (JSMO), Korea (KSMO), Malaysia (MOS), the Philippines (PSMO), Singapore (SSO), Taiwan (TOS) and Thailand (TSCO), coordinated by ESMO and the Japanese Society of Medical Oncology (JSMO). The voting was based on scientific evidence and was independent of the current treatment practices, drug access restrictions and reimbursement decisions in the different Asian regions represented by the 10 oncological societies. The latter are discussed separately in the manuscript. The aim is to provide guidance for the optimisation and harmonisation of the management of patients with GC across the different regions of Asia, drawing on the evidence provided by both Western and Asian trials, whilst respecting the differences in screening practices, molecular profiling and age and stage at presentation. Attention is drawn to the disparity in the drug approvals and reimbursement strategies, between the different regions of Asia.

Immune checkpoint inhibitors (ICIs) with nivolumab and pembrolizumab are promising agents for advanced hepatocellular carcinoma (HCC) but lack of effective biomarkers. We aimed to investigate the potential predictors of response and factors associated with overall survival (OS) for ICI treatment in unresectable HCC patients. Ninety-five patients who received nivolumab or pembrolizumab for unresectable HCC were enrolled for analyses. Radiologic evaluation was based on RECIST v1.1. Factors associated with outcomes were analyzed. Of 90 patients with evaluable images, the objective response rate (ORR) was 24.4%. Patients at Child–Pugh A or received combination treatment had higher ORR. Early alpha-fetoprotein (AFP) >10% reduction (within 4 weeks) was the only independent predictor of best objective response (odds ratio: 7.259, p = 0.001). For patients with baseline AFP ≥10 ng/mL, significantly higher ORR (63.6% vs. 10.2%, p < 0.001) and disease control rate (81.8% vs. 14.3%, p < 0.001) were observed in those with early AFP reduction than those without. In addition, early AFP reduction and albumin-bilirubin (ALBI) grade or Child–Pugh class were independent factors associated with OS in different models. In conclusion, a 10-10 rule of early AFP response can predict objective response and survival to ICI treatment in unresectable HCC. ALBI grade and Child–Pugh class determines survival by ICI treatment.

Background Immunotherapy with immune checkpoint inhibitor (ICI) is a promising treatment for unresectable hepatocellular carcinoma (HCC). However, whether ICIs would have the risk of hepatitis B virus (HBV) reactivation and the necessary of nucleos(t)ide analogs (NUCs) prophylaxis are still unclear. We aimed to investigate the role of NUCs prophylaxis in HBV-infected patients who underwent ICIs treatment. Methods The study was a retrospective prospective design to review and follow-up consecutive 62 patients with chronic hepatitis B or resolved HBV infection who had received ICIs treatment for the unresectable HCC. Of them, 60 patients with documented baseline serum HBV DNA value were classified into three categories according to the baseline HBV viral load and the status of antiviral therapy before ICI treatment. The clinical status, including tumor response, viral kinetics and liver function, was recorded and investigated. Results No HBV reactivation occurred in the 35 patients with HBV DNA ≤100 IU/mL on NUCs therapy. Of the 19 patients with HBV DNA >100 IU/mL who started NUCs simultaneously with ICI treatment, none encountered HBV reactivation during the immunotherapy. Of the six HBV patients without NUCs treatment, three had a greater than 1 log decrease in HBV viral load, and one maintained his serum HBV DNA in undetectable status during ICI treatment. Eventually, one out of six experienced HBV reactivation after 9 weeks of ICI treatment. Conclusion No patients on antiviral therapy developed HBV reactivation, and one out of six not receiving antiviral therapy had HBV reactivation. HBV viral load higher than 100 IU/mL is safe and not a contraindication for ICI treatment for HCC, if NUCs can be coadministrated.

Background: Immunological checkpoint blockade is effective in treating various malignancies. Identifying predictive biomarkers to assist patient selection for immunotherapy has become a priority in both clinical and research settings.Methods: Mutations in patients who responded to immunotherapy were identified through next-generation sequencing. Relationships among protein kinase, DNA-activated, catalytic polypeptide (PRKDC) mutations, mutation load and microsatellite instability (MSI) were analyzed using datasets from The Cancer Genome Atlas. These relationships were validated by conducting an in vitro study and by using tissue samples from 34 patients with gastric cancer. The CT26 animal model was used to evaluate the role of PRKDC as a predictive biomarker and the efficacy of the DNA-PK inhibitor.Results: From the published literature, we found that among patients whose tumors harboredPRKDCmutations, 75%, 53.8%, and 50% of those with lung cancer, melanoma, and renal cell carcinoma, respectively, responded to immunotherapy. Most of these mutations were truncating and located in functional domains or in a destabilizing PRKDC protein structure. Additional analysis showed that aPRKDCmutation was significantly associated with a high mutation load in cervical cancer, colon adenocarcinoma, head and neck squamous cell carcinoma, lung adenocarcinoma, gastric adenocarcinoma and endometrial cancer. Patients with gastric cancer or colon cancer harboringPRKDCmutations were also highly associated with MSI-high status. Finally, we found that knockout PRKDC or DNA-PK inhibitor (PRKDCencodes the catalytic subunit of DNA-dependent protein kinase) enhanced the efficacy of the anti-programmed cell death protein one pathway monoclonal antibody in the CT26 animal model.Conclusions: PRKDC is not only a predictive biomarker but also a drug target for immune checkpoint inhibitors.

PURPOSE: Biliary tract cancers (BTCs) harbor an immunosuppressed tumor microenvironment and respond poorly to PD-1/PD-L1 inhibitors. Bevacizumab (anti–vascular endothelial growth factor) plus chemotherapy can promote anticancer immunity, augmenting response to PD-L1 inhibition. PATIENTS AND METHODS: This randomized, double-blind, proof-of-concept phase II study enrolled patients (n = 162) with previously untreated advanced BTC (IMbrave151; ClinicalTrials.gov identifier: NCT04677504 ). Patients were randomly assigned 1:1 to receive cycles of atezolizumab (1,200 mg) plus bevacizumab (15 mg/kg) or atezolizumab plus placebo once every 3 weeks until disease progression or unacceptable toxicity. All patients received cisplatin (25 mg/m ² ) plus gemcitabine (1,000 mg/m ² ; cisplatin plus gemcitabine [CisGem]) on days 1 and 8 once every 3 weeks for up to eight cycles. Stratification of patients was by disease status, geographic region, and primary tumor location. The primary end point was progression-free survival (PFS). No formal hypothesis testing was performed. Exploratory correlative biomarker analysis was undertaken using transcriptome analysis (n = 95) and mutation profiling (n = 102) on baseline tumor samples. RESULTS: Between February and September 2021, 162 patients were enrolled. Median PFS was 8.3 months in the bevacizumab arm and 7.9 months in the placebo arm (stratified hazard ratio [HR], 0.67 [95% CI, 0.46 to 0.95]). Median overall survival (OS) was 14.9 and 14.6 months in the bevacizumab and placebo arms, respectively (stratified HR, 0.97 [95% CI, 0.64 to 1.47]). The incidence of grade 3 or 4 adverse events was 74% in both arms. High VEGFA gene expression was associated with improved PFS (HR, 0.44 [95% CI, 0.23 to 0.83]) in the bevacizumab arm versus placebo. CONCLUSION: In unselected patients with advanced BTC, adding bevacizumab to atezolizumab plus CisGem modestly improves PFS but not OS. High VEGFA gene expression may represent a predictive biomarker of benefit from atezolizumab/bevacizumab, warranting further investigation.

Background: The form of microsatellite instability (MSI) affecting tetranucleotide repeats known as elevated microsatellite alterations at selected tetranucleotide repeats (EMAST) has emerged as a new potential biomarker in multiple cancers. In colorectal cancer (CRC), the correlation between EMAST and MSI mutations remain inconclusive. Materials and Methods: We evaluated 1,505 patients with CRC using five EMAST markers (D20S82, D20S85, D8S321, D9S242, and MYCL1) and the Bethesda panel of MSI markers. Most commonly, mutations involved in CRCs were identified by MassArray Assay, and DNA repair genes were analyzed by next-generation sequencing. Clinical characteristics and prognostic relevance were correlated with EMAST and MSI. Results: Tumors that were EMAST positive and MSI high (MSI-H) were detected in 159 (10.6%) and 154 (10.2%) of 1,505 patients with CRC. Patients were divided into four groups according to EMAST and MSI status (EMAST-positive and MSI-H, EMAST-positive and microsatellite-stable [MSS], EMAST-negative and MSI-H, and EMAST-negative and MSS). The EMAST-positive and MSI-H group was associated with female predominance, higher prevalence of proximal colon tumors, early stage tumors, poorly differentiated tumors, mucinous histology, and higher incidence of mutations in PI3KCA, BRAF, TGFBR, PTEN, and AKT1 compared with other groups. Furthermore, compared with only EMAST-positive tumors or only MSI-H tumors, tumors that were both EMAST-positive and MSI-H had a higher frequency of MLH1, MSH3, MSH6, PMS2, and EXO1 gene mutations. Finally, the presence of EMAST-positive and MSI-H tumors was a good prognostic indicator in CRC. Conclusion: High mutations in several DNA repair genes in EMAST-positive and MSI-H tumors suggest that this subtype of CRC might be more suitable for treatment with immune therapy. Implications for Practice: Elevated microsatellite alterations at selected tetranucleotide repeats (EMAST) is a unique molecular subtype of colorectal cancer (CRC). The current study demonstrated that the EMAST-positive and MSI-high (MSI-H) group was associated with female predominance, higher prevalence of proximal colon tumors, early stage tumors, poorly differentiated tumors, mucinous histology, and higher incidence of mutations in PI3KCA, BRAF, TGFBR, PTEN, and AKT1 compared with other groups. Most importantly, high mutations in DNA repair genes and MSI-related genes in EMAST-positive and MSI-H tumors suggest that this subtype of CRC might be more suitable for treatment with immune therapy compared with MSI-H tumors alone.