Trending Topics in Gastroenterology | GastroAGI

Zanidatamab Redefines First-Line HER2+ GEA Therapy : NEJM | May 2026

Introduction Gastroesophageal Adenocarcinoma remains an aggressive malignancy with limited long-term survival despite HER2-directed therapy. Since the ToGA era, trastuzumab-based chemotherapy has remained the standard first-line treatment, but therapeutic resistance and incomplete durability of response continue to limit outcomes. Problem Statement Whether next-generation HER2-targeted strategies can surpass trastuzumab-based therapy and meaningfully improve survival in HER2-positive gastroesophageal adenocarcinoma has remained a major unanswered clinical question. Summary This landmark phase 3 HERIZON-GEA-01 trial evaluated Zanidatamab combined with chemotherapy, with or without Tislelizumab, against standard trastuzumab plus chemotherapy in previously untreated HER2-positive advanced gastroesophageal adenocarcinoma. Zanidatamab is a dual HER2-targeted bispecific antibody engineered to simultaneously bind extracellular domains 2 and 4 of HER2, thereby enhancing receptor clustering, internalization and immune-mediated cytotoxicity compared with conventional single-epitope HER2 targeting. The study demonstrated a major improvement in progression-free survival with both zanidatamab-containing regimens. Median progression-free survival increased from 8.1 months with trastuzumab-based therapy to 12.4 months with both zanidatamab-containing arms, representing a clinically meaningful delay in disease progression. Most importantly, the combination of zanidatamab, tislelizumab and chemotherapy achieved a statistically significant overall survival advantage over trastuzumab-based therapy, with median overall survival extending to 26.4 months versus 19.2 months. Although the zanidatamab-chemotherapy arm numerically improved overall survival, statistical significance was not reached at this interim analysis, suggesting that immune checkpoint inhibition may provide an additive survival benefit in this setting. These findings are highly relevant because durable survival improvements in metastatic gastroesophageal cancer have historically been difficult to achieve. Crossing the two-year median survival threshold in HER2-positive disease represents a major therapeutic advance. The study additionally reinforces the evolving importance of combining targeted therapy with immunotherapy in upper gastrointestinal malignancies. HER2-directed treatment may enhance tumor immunogenicity, potentially amplifying responsiveness to PD-1 blockade. From a toxicity standpoint, zanidatamab-containing regimens demonstrated manageable but increased gastrointestinal toxicity, particularly diarrhea. Grade 3 or higher adverse events were common across all treatment groups, reflecting the intensity of combination systemic therapy in advanced gastroesophageal cancer. Importantly, no unexpected safety signals emerged, supporting the feasibility of integrating dual HER2 targeting with checkpoint inhibition and chemotherapy in frontline practice. The trial also highlights the rapid evolution of antibody engineering in gastrointestinal oncology. Unlike trastuzumab, bispecific antibodies such as zanidatamab provide multi-epitope HER2 engagement, potentially overcoming mechanisms of receptor heterogeneity and resistance. Clinically, the results are likely to reshape frontline management algorithms for HER2-positive gastroesophageal adenocarcinoma. The zanidatamab–tislelizumab–chemotherapy regimen now emerges as a strong candidate for a new first-line standard of care. The findings are also important within the broader context of precision GI oncology, where biomarker-selected therapies are increasingly driving meaningful survival gains in traditionally treatment-refractory malignancies. Future analyses will be important to clarify durability of benefit, subgroup-specific efficacy, mechanisms of resistance and optimal sequencing with subsequent HER2-directed therapies and antibody-drug conjugates. Overall, HERIZON-GEA-01 establishes zanidatamab-based therapy as a major advance in HER2-positive gastroesophageal adenocarcinoma, demonstrating substantial progression-free survival benefit and clinically meaningful overall survival improvement when combined with tislelizumab and chemotherapy.

ctDNA Predicts Early Multiorgan Recurrence in CRLM : BJS | May 2026

Introduction Colorectal Liver Metastases frequently recur despite curative-intent surgery, with nearly half of patients developing relapse within the first postoperative year. Early identification of biologically aggressive disease remains a major unmet need in surgical oncology. Problem Statement Reliable preoperative biomarkers capable of identifying patients with resectable colorectal liver metastases at high risk for rapid multiorgan recurrence and poor survival are lacking. Summary This MIRACLE cohort study evaluated pretreatment circulating tumour DNA using the modified fast aneuploidy screening test-sequencing system (mFast-SeqS) in chemotherapy-naïve patients undergoing curative-intent treatment for colorectal liver metastases. Patients with high pretreatment ctDNA aneuploidy scores experienced markedly worse oncologic outcomes compared with ctDNA-low patients. Recurrence-free survival and overall survival were both significantly reduced, with ctDNA-high patients demonstrating substantially higher rates of rapid relapse. Most notably, elevated ctDNA was strongly associated with early multiorgan recurrence within the first postoperative year. This finding is clinically important because multiorgan relapse often reflects occult systemic dissemination not fully captured by conventional imaging or clinicopathologic risk models. The prognostic value of ctDNA remained independently significant on multivariable analysis for recurrence-free survival, multiorgan recurrence and overall survival, reinforcing its role as a robust biologic marker of aggressive metastatic disease. Importantly, the study focused specifically on chemotherapy-naïve patients, reducing confounding effects from perioperative systemic treatment and providing a clearer assessment of baseline tumour biology. A major practical strength of the work is the use of mFast-SeqS, an affordable and minimally invasive sequencing platform based on genome-wide aneuploidy detection rather than individualized mutation tracking. This may improve scalability and real-world implementation compared with more complex personalized ctDNA assays. The findings support the growing concept that ctDNA reflects minimal residual systemic disease burden even before surgery. Elevated pretreatment ctDNA likely identifies patients with biologically disseminated micrometastatic disease despite technically resectable liver metastases. Clinically, these results may eventually influence perioperative decision-making. Patients with high ctDNA burden could potentially benefit from intensified systemic therapy, closer surveillance or alternative multimodal treatment strategies rather than surgery alone. The association with multiorgan recurrence is particularly relevant because current surgical selection criteria rely heavily on anatomical resectability and radiologic disease burden, which incompletely capture tumour biology. This study therefore contributes to the ongoing transition from anatomy-based toward biology-driven management of metastatic colorectal cancer. The findings also align with broader precision oncology trends where liquid biopsy technologies increasingly guide risk stratification, treatment escalation and postoperative surveillance strategies across solid tumors. Future studies will need to determine whether ctDNA-guided perioperative treatment adaptation can improve outcomes and whether serial postoperative monitoring further refines recurrence prediction. Importantly, prospective validation and integration with molecular, radiologic and clinicopathologic risk models will be essential before widespread implementation into routine surgical oncology practice. Overall, this MIRACLE cohort study demonstrates that elevated pretreatment ctDNA measured by mFast-SeqS independently predicts rapid multiorgan recurrence and inferior survival in resectable colorectal liver metastases, supporting ctDNA as a promising biomarker for biologic risk stratification before curative-intent surgery.

Real-World Data Support Transplant Benefit in Unresectable CRLM : Liver Transpl | Feb 2026

Introduction Colorectal Liver Metastases have historically been considered a contraindication to Liver Transplantation because of high recurrence risk and limited organ availability. However, modern systemic therapies, refined biologic selection and highly favorable outcomes from the TransMet trial have reignited interest in transplantation for carefully selected unresectable CRLM patients. The TransMet study reported unprecedented five-year survival exceeding 70%, challenging conventional transplant oncology paradigms. Problem Statement Although TransMet demonstrated promising survival outcomes, questions remain regarding external validity, reproducibility in real-world populations and the actual magnitude of transplant benefit compared with continued systemic chemotherapy. Robust prognostic stratification tools for patient selection also remain underdeveloped. Summary This multicenter international study provides the first external validation assessment of the TransMet selection criteria using a real-world cohort of 61 patients with unresectable CRLM undergoing liver transplantation across seven centers. Investigators used matching-adjusted indirect comparison methods to improve comparability between the real-world transplant cohort and the original TransMet population. The results demonstrated remarkable consistency with the original TransMet findings. Five-year restricted mean survival time in the weighted real-world cohort closely mirrored outcomes observed in the TransMet liver transplantation arm, supporting reproducibility of the survival benefit outside specialized trial settings. Sensitivity analyses accounting for residual imbalance yielded similarly favorable long-term survival estimates. Importantly, the study quantified transplant benefit relative to chemotherapy alone. Liver transplantation was associated with an estimated five-year survival gain exceeding 22 months compared with systemic therapy, reinforcing the substantial clinical impact of transplantation in highly selected patients with unresectable CRLM. The analysis additionally identified several biologic factors associated with inferior post-transplant survival. KRAS Mutation emerged as one of the strongest adverse prognostic markers, consistent with prior colorectal oncology literature linking KRAS alterations to aggressive tumor biology and treatment resistance. Right-sided primary tumors also demonstrated poorer outcomes, further supporting the increasingly recognized prognostic divergence between right- and left-sided colorectal cancers. Elevated carcinoembryonic antigen levels additionally appeared to predict worse post-transplant outcomes, suggesting that tumor biology rather than technical unresectability alone should drive transplant candidate selection. These findings strengthen the evolving concept of transplant oncology as a biologically guided discipline integrating molecular and clinical risk profiling. The study is particularly important because it moves beyond simple survival reporting toward formal estimation of transplant benefit — a critical consideration given ongoing ethical concerns regarding organ allocation. Demonstrating substantial survival extension relative to systemic therapy strengthens the rationale for considering unresectable CRLM within future liver allocation frameworks, especially as outcomes now approach or exceed those achieved in several accepted transplant indications. Nevertheless, the authors appropriately emphasize the need for larger multicenter datasets and more refined prognostic models. Recurrence after transplantation remains common in CRLM, and optimal integration of molecular biomarkers, chemotherapy response and disease kinetics into candidate selection algorithms is still evolving. Overall, this first real-world validation study supports the external reproducibility of the TransMet trial findings and demonstrates meaningful transplant benefit in selected patients with unresectable colorectal liver metastases. The data further reinforce the emerging role of biologically driven transplant oncology and support continued evaluation of CRLM within future liver transplantation allocation and selection strategies.

TQB2102 Shows Strong Activity Across HER2-Expressing Tumors : Ann Oncol | May 2026

Introduction Antibody-Drug Conjugate development has rapidly transformed treatment paradigms for HER2-expressing malignancies. However, resistance, heterogeneous HER2 expression and toxicity remain major limitations of currently available HER2-targeted therapies. TQB2102 is a next-generation biparatopic HER2 antibody-drug conjugate simultaneously targeting extracellular domain 2 and extracellular domain 4 of HER2 while delivering a topoisomerase I inhibitor payload through an enzyme-cleavable linker. Problem Statement Current HER2-directed ADCs demonstrate variable activity across tumor types and limited efficacy in HER2-low disease or brain metastases. Novel HER2-targeting strategies capable of improving receptor binding, internalization and payload delivery while maintaining manageable toxicity profiles are needed. Summary This first-in-human multicenter phase I trial evaluated TQB2102 in 195 patients with advanced solid tumors, including metastatic breast cancer, colorectal cancer and gastric/gastroesophageal junction adenocarcinoma. The study incorporated both dose-escalation and dose-expansion cohorts using administration every three weeks. TQB2102 demonstrated a favorable safety profile across all dose levels. No dose-limiting toxicities occurred, the maximum tolerated dose was not reached and recommended phase II doses were established at 6.0 mg/kg and 7.5 mg/kg. The most frequent grade ≥3 toxicities were hematologic, including neutropenia, leukopenia and anemia. Importantly, only one patient developed treatment-related interstitial lung disease, a particularly notable finding given ILD concerns with several currently approved HER2 ADCs. Preliminary antitumor efficacy was highly encouraging across multiple HER2-expressing tumor types. Objective response rates exceeded 50% in metastatic breast cancer and approached 40% in both colorectal cancer and gastric/gastroesophageal junction adenocarcinoma. Particularly striking activity was observed in HER2-low metastatic breast cancer, where response rates remained robust despite lower receptor expression. These findings reinforce the possibility that biparatopic HER2 targeting may enhance receptor clustering, internalization and intracellular payload delivery beyond conventional monospecific HER2 ADCs. The activity observed in patients with brain metastases was especially noteworthy. Objective response rates reached 70% in HER2-positive breast cancer brain metastases and 50% even among HER2-low cases, suggesting substantial intracranial activity. Given the major unmet need for effective CNS-penetrant HER2 therapies, these findings may have important implications for future metastatic breast cancer management strategies. Mechanistically, biparatopic targeting of HER2 ECD2 and ECD4 likely improves receptor engagement and enhances lysosomal trafficking compared with traditional single-epitope HER2 antibodies. Combined with a membrane-permeable topoisomerase I inhibitor payload, this design may additionally promote bystander killing within heterogeneous HER2-expressing tumors, potentially explaining activity in HER2-low disease settings. Overall, this first-in-class phase I study positions TQB2102 as a highly promising next-generation HER2 ADC with encouraging efficacy across multiple advanced solid tumors, including HER2-low disease and CNS metastases. The manageable toxicity profile and broad antitumor activity support ongoing phase III development, particularly in HER2-low metastatic breast cancer.

Adjuvant HAI Oxaliplatin Improves Liver Control After CRLM Surgery : J Clin Oncol | May 2026

Introduction Recurrence after curative-intent surgery for Colorectal Liver Metastases remains common, particularly in patients with high metastatic burden. The liver represents the dominant site of relapse, even after modern systemic chemotherapy and complete resection or ablation. Hepatic Arterial Infusion allows selective administration of high-dose chemotherapy directly to hepatic tumors while limiting systemic exposure and has shown promising activity in metastatic colorectal cancer. However, prospective randomized data evaluating adjuvant HAI after resection of extensive CRLM have been limited. Problem Statement Patients undergoing surgery for four or more colorectal liver metastases remain at extremely high risk for hepatic recurrence despite perioperative systemic chemotherapy. Whether postoperative HAI chemotherapy can improve hepatic disease control and survival outcomes compared with standard intravenous chemotherapy alone has remained uncertain. Summary This randomized phase II trial evaluated adjuvant hepatic arterial infusion of oxaliplatin combined with systemic LV5FU2 following curative-intent surgery or ablation of at least four colorectal liver metastases. Ninety-nine high-risk patients previously treated with preoperative systemic chemotherapy were randomized to receive oxaliplatin via hepatic arterial infusion or standard intravenous administration, both combined with intravenous fluorouracil/leucovorin. After nearly five years of median follow-up, hepatic arterial infusion significantly improved hepatic recurrence-free survival, doubling median liver-specific disease control compared with standard intravenous therapy. Median hepatic recurrence-free survival reached 25 months in the HAI arm versus 12 months with intravenous chemotherapy alone. Overall recurrence-free survival was also significantly prolonged, demonstrating broader disease-control benefits beyond isolated liver recurrence reduction. Although overall survival did not reach statistical significance, clinically meaningful improvements were observed. Median overall survival approached 74 months in the HAI group compared with 57 months in the intravenous chemotherapy group, with five-year overall survival rates of 62% versus 47%, respectively. These findings suggest a potentially important long-term survival advantage that may become clearer in larger phase III validation studies. As expected, intensified regional chemotherapy was associated with higher toxicity. Grade 3–4 adverse events occurred more frequently in the HAI arm, although treatment remained feasible overall, with comparable completion rates between groups and no treatment-related deaths. Importantly, toxicity appeared manageable within experienced multidisciplinary hepatobiliary oncology programs. The study reinforces the concept that recurrence after CRLM surgery is predominantly liver-driven and that intensified liver-directed adjuvant strategies may substantially alter postoperative disease biology in selected high-risk patients. The findings are particularly relevant for patients with extensive bilobar disease or multiple metastases, who remain at greatest risk for early hepatic relapse despite technically curative surgery. Overall, this important randomized study supports postoperative oxaliplatin-based hepatic arterial infusion as a promising adjuvant strategy for high-risk colorectal liver metastases and provides strong justification for ongoing phase III evaluation of regional chemotherapy intensification after CRLM resection.

EXTEND Trial Supports MDT in Oligometastatic Disease : J Clin Oncol | May 2026

Introduction The concept of oligometastatic disease proposes that selected patients with limited metastatic burden may benefit from aggressive local treatment directed at metastatic sites in addition to systemic therapy. Metastasis-Directed Therapy, most commonly stereotactic radiotherapy, has demonstrated promising outcomes in several tumor-specific studies, but whether its benefit extends consistently across multiple solid tumor histologies has remained uncertain. The phase II EXTEND trial evaluated the addition of MDT to standard systemic therapy across several oligometastatic solid tumor “baskets.” Problem Statement Although prior studies suggested progression-free survival benefits with local ablative therapy in oligometastatic disease, most trials were small, histology-specific and underpowered for broad oncologic applicability. Reliable biomarkers defining true oligometastatic biology and predictors of MDT responsiveness also remain lacking. Summary The multicenter randomized phase II EXTEND trial enrolled patients with one to five metastatic lesions across six tumor-histology baskets including pancreatic, breast, renal and prostate cancers. Patients were randomized to receive standard systemic therapy alone or combined with metastasis-directed therapy, predominantly stereotactic radiotherapy. After a median follow-up exceeding four years, the addition of MDT significantly improved progression-free survival across all baskets combined. Importantly, this benefit persisted even after exclusion of prostate cancer cohorts, addressing concerns that highly radiosensitive prostate disease might disproportionately drive positive results. Histology-specific analyses demonstrated particularly strong efficacy signals in pancreatic cancer, prostate cancer and the heterogeneous “Other” basket, whereas breast and kidney cancer cohorts yielded less definitive results. These findings support the possibility that oligometastatic biology and sensitivity to local ablative therapy vary substantially according to tumor histology. The study also provided important translational insights. Detectable circulating tumor DNA (ctDNA) at baseline correlated with inferior progression-free and overall survival, whereas ctDNA clearance three months after treatment was associated with improved outcomes. These findings suggest that molecular residual disease assessment may help refine future definitions of oligometastatic disease and identify patients most likely to benefit from aggressive local therapy. Additionally, immune profiling demonstrated enhanced systemic immune activation among patients receiving MDT combined with systemic therapy, particularly within tumor baskets showing the greatest clinical benefit. These observations reinforce the hypothesis that focal radiotherapy may augment systemic antitumor immunity through immunomodulatory and abscopal mechanisms rather than merely improving local disease control. Overall, the EXTEND trial provides one of the strongest multicancer randomized datasets supporting incorporation of metastasis-directed therapy into management strategies for selected oligometastatic solid tumors. The findings support future phase III validation studies and highlight ctDNA-guided stratification and immune activation as important future directions in precision oligometastatic oncology.

Perioperative Toripalimab Improves Survival in Resectable Gastric/GEJ Cancer : J Clin Oncol | May 2026

Introduction Perioperative chemotherapy remains the standard treatment approach for locally advanced resectable gastric and gastroesophageal junction (GEJ) adenocarcinoma. However, recurrence rates remain high despite curative-intent surgery and systemic therapy, particularly because of peritoneal metastasis. Immune checkpoint inhibitors have demonstrated meaningful survival benefits in advanced gastric cancer, prompting investigation in earlier perioperative settings. Problem Statement Although early studies suggested improved pathological response with perioperative immunotherapy, robust long-term survival data in resectable gastric and GEJ cancer remain limited. It is unclear whether addition of PD-1 blockade to perioperative chemotherapy translates into durable event-free and overall survival benefit. Summary This 3-year follow-up analysis of the randomized phase II NEOSUMMIT-01 trial demonstrated significant long-term survival benefits with perioperative toripalimab plus oxaliplatin-based chemotherapy in patients with locally advanced gastric or GEJ adenocarcinoma. Compared with chemotherapy alone, the addition of the PD-1 inhibitor toripalimab significantly improved both event-free survival and overall survival, with approximately three-quarters of patients remaining event-free at 3 years. Importantly, the survival benefit persisted even after excluding patients with deficient mismatch repair tumors, indicating efficacy beyond highly immunotherapy-sensitive MSI-H/dMMR disease subsets. The therapeutic advantage was also consistently observed across most predefined clinical subgroups. A particularly notable finding was the marked reduction in peritoneal metastasis, historically one of the most challenging recurrence patterns in gastric cancer. The toripalimab-containing regimen nearly halved overall relapse rates and substantially reduced peritoneal dissemination compared with chemotherapy alone, suggesting improved micrometastatic disease control. The study further strengthens growing evidence supporting oxaliplatin-based chemotherapy backbones as favorable partners for perioperative immunotherapy in gastric cancer. Unlike the negative survival findings observed with perioperative pembrolizumab in KEYNOTE-585, the NEOSUMMIT-01 results align more closely with the positive MATTERHORN trial, collectively supporting integration of immunotherapy into curative-intent treatment paradigms. Although limited by its phase II design and predominantly Asian study population, the trial provides compelling evidence that perioperative toripalimab combined with SOX or CapOx chemotherapy may represent a promising new treatment strategy for resectable locally advanced gastric and GEJ cancers.

Advanced Adenomas Detected Frequently in Young Endurance Runners : Cancer Epidemiol | May 2026

Introduction Regular physical activity is generally associated with reduced colorectal cancer (CRC) risk. However, extreme endurance exercise may produce repetitive gastrointestinal stress through splanchnic hypoperfusion, ischemia–reperfusion injury, mucosal inflammation and occult gastrointestinal bleeding. Whether chronic exposure to these physiologic insults influences colorectal neoplasia risk remains poorly understood. Problem Statement Although gastrointestinal bleeding and ischemic colitis are recognized complications of endurance running, data linking high-volume endurance exercise with colorectal adenomas or advanced neoplasia are lacking. Understanding whether endurance athletes harbor increased rates of premalignant colorectal lesions could influence screening and evaluation strategies, particularly in younger individuals with post-exercise rectal bleeding. Summary This prospective hypothesis-generating study evaluated colonoscopic findings in endurance runners aged 35–50 years with substantial marathon or ultramarathon exposure. Adenomas were identified in over 40% of participants, while advanced adenomas were detected in 15%, substantially exceeding historical screening benchmarks for average-risk younger adults. Importantly, no colorectal cancers were identified. Most advanced lesions were right-sided and frequently exhibited high-risk features including large size, tubulovillous histology or sessile serrated morphology. Post-exercise rectal bleeding was significantly more common among runners with advanced adenomas, suggesting that gastrointestinal bleeding after endurance exercise should not be routinely dismissed as benign “runner’s colitis.” Notably, advanced adenomas were also detected in asymptomatic runners without bleeding, indicating that clinically silent lesions may occur in this population. Despite the observed adenoma burden, the study did not demonstrate a clear relationship between training intensity and lesion prevalence, underscoring the exploratory nature of the findings. The authors propose several biologically plausible mechanisms including repetitive ischemia–reperfusion injury, oxidative stress, microbiome alterations and mucosal regenerative hyperproliferation. However, the study’s single-arm design, modest sample size and potential selection bias preclude causal inference. Overall, the findings generate an important hypothesis that extreme endurance running may be associated with increased prevalence of advanced colorectal precursor lesions and support larger controlled studies evaluating colorectal neoplasia risk in endurance athletes.

FDA Expands Precision Oncology Approvals Across Hematologic and Solid Tumors : Oncol Times | May 2026

Introduction Recent FDA approvals continue to accelerate the shift toward biomarker-driven and targeted cancer therapy across hematologic malignancies and solid tumors. Novel immunotherapies and molecularly targeted agents are increasingly improving outcomes in diseases previously associated with limited therapeutic options. Problem Statement Despite major advances in oncology, patients with relapsed multiple myeloma, BRAF V600E–mutated metastatic colorectal cancer and HER2-mutated non-small cell lung cancer continue to face poor long-term outcomes and therapeutic resistance. Expanding effective targeted treatment options remains a major unmet clinical need. Summary This FDA update highlights three important regulatory approvals that reinforce the growing role of precision oncology and immune-directed therapy. Teclistamab combined with daratumumab hyaluronidase demonstrated substantial progression-free and overall survival benefit in relapsed or refractory multiple myeloma, establishing an effective early-line bispecific antibody–based strategy. However, the therapy carries important immune-related toxicities including cytokine release syndrome and neurotoxicity, necessitating REMS-based monitoring. In metastatic colorectal cancer, encorafenib combined with cetuximab and fluorouracil-based chemotherapy received traditional approval for treatment-naïve BRAF V600E–mutated disease following strong survival improvements in the BREAKWATER trial. The findings further validate BRAF-targeted therapy as a frontline precision treatment strategy in this historically aggressive colorectal cancer subtype. Meanwhile, zongertinib received accelerated approval for HER2-mutated advanced non-small cell lung cancer after demonstrating high objective response rates and durable responses in previously untreated patients. Collectively, these approvals illustrate several important trends in modern oncology: earlier integration of targeted therapies, expansion of biomarker-defined treatment paradigms and increasing reliance on molecular profiling to guide therapeutic selection. The update also underscores the continuing balance between efficacy and toxicity management as increasingly potent immune and targeted agents move into earlier lines of treatment.

PD-(L)1 Plus Chemotherapy Benefits Advanced Gastric Cancer Across Regions : Clin Transl Gastroenterol | May 2026

Introduction Immune checkpoint inhibitors targeting programmed cell death protein-(ligand) 1 (PD-[L]1) have transformed first-line treatment of advanced gastric cancer (GC) and gastroesophageal junction cancer (GEJC). However, important regional differences in epidemiology, tumor biology, clinical presentation and treatment practices between Asian and non-Asian populations have raised questions regarding the global generalizability of chemoimmunotherapy outcomes. Problem Statement Although PD-(L)1 inhibitors combined with chemotherapy are widely incorporated into treatment guidelines, uncertainty persists regarding whether survival benefits differ between Asian and non-Asian patients with advanced GC/GEJC. Clarifying these regional outcomes is critical for global treatment standardization, regulatory decision-making and equitable access to immunotherapy. Summary This large meta-analysis of phase III randomized trials demonstrates that first-line PD-(L)1 inhibitors combined with chemotherapy significantly improve overall survival and progression-free survival in advanced HER2-negative GC/GEJC irrespective of Asian or non-Asian regional background. Across more than 6700 patients, survival benefits were remarkably consistent between geographic populations, supporting the broad applicability of chemoimmunotherapy across diverse clinical settings. Although progression-free survival appeared numerically more favorable in Asian populations, the difference was not statistically significant and may partly reflect variations in disease burden and patterns of recurrent versus de novo metastatic disease at study entry. Importantly, treatment-related adverse events remained comparable between immunotherapy-based regimens and chemotherapy-alone controls, reinforcing the acceptable safety profile of combined checkpoint inhibition. The findings also support the concept that immunotherapy benefit in advanced GC/GEJC is primarily biology-driven rather than geography-driven. Sensitivity analyses excluding negative studies and PD-L1–enriched cohorts did not materially alter outcomes, strengthening the robustness of the conclusions. The review further highlights persistent limitations in current evidence, including inconsistent reporting of biomarker-defined subgroups, regional genomic differences and immune-related adverse events. Overall, this study provides strong evidence supporting global use of first-line PD-(L)1 inhibitor plus chemotherapy strategies in advanced gastric and gastroesophageal junction adenocarcinoma and may help reduce disparities in worldwide access to modern immunotherapy.