That question took on renewed urgency at the 2024 meeting of the FDA Oncologic Drugs Advisory Committee, which re-examined the comparative efficacy of PD-1 inhibitors plus chemotherapy across PD-L1 expression levels. The committee concluded that patients whose tumors express PD-L1 at a combined positive score or tumor area positivity score of 10 or higher derive the clearest benefit from PD-1 inhibitors, while those scoring below 1 show no meaningful improvement over chemotherapy alone. The large intermediate zone between those thresholds remains contested, and even in higher-expression groups certain populations, notably patients with liver metastases, appear relatively resistant to single-target immunotherapy. Against this backdrop, a new network meta-analysis published in Cancer Reports offers the first systematic indirect comparison of a different immunotherapy architecture: cadonilimab, a tetravalent bispecific antibody that blocks both PD-1 and CTLA-4 within a single molecule.

The research team, registered in the PROSPERO repository and conducted under PRISMA guidelines, searched PubMed, Web of Science, Embase and the Cochrane Library from inception through December 31, 2024, supplementing the database results with conference abstracts from ASCO, ESMO and AACR and with FDA advisory committee documents. Their inclusion criteria were deliberately strict: only Phase III randomized controlled trials in pathologically confirmed, previously untreated, HER2-negative gastric or gastroesophageal junction cancer qualified, and every experimental arm had to combine chemotherapy with either a single-agent anti-PD-(L)1 antibody or the anti-PD-1/CTLA-4 bispecific antibody cadonilimab. From an initial pool of 4,089 publications, screening narrowed the field to eight trials that met all criteria: KEYNOTE-062, ATTRACTION-4, CheckMate-649, KEYNOTE-859, GEMSTONE-303, ORIENT-16, COMPASSION-15 and RATIONALE 305. Together these trials enrolled 7,127 patients, of whom 3,572 received chemotherapy plus an immune checkpoint inhibitor and 3,555 received chemotherapy with placebo.

Because no head-to-head trial has ever compared cadonilimab with a PD-(L)1 antibody, the investigators used a frequentist network meta-analysis, treating all platinum-fluoropyrimidine doublet backbones—XELOX, FOLFOX, SOX and fluorouracil-platinum—as a common chemotherapy comparator node, an approach supported by prior noninferiority trials and systematic reviews showing these regimens are clinically interchangeable. Overall survival, defined as time from randomization to death from any cause, served as the primary endpoint, with progression-free survival and Grade 3 to 5 treatment-related and serious adverse events as secondary measures. Risk of bias was low across the included studies when assessed with the Cochrane RoB 2 tool, and all trials were analyzed on an intention-to-treat basis. Because the network was star-shaped, with cadonilimab connected to the PD-(L)1 inhibitors only through the shared chemotherapy node, formal inconsistency testing was not possible, a structural limitation the authors acknowledge openly.

The headline finding is striking. In the intention-to-treat population, every immunotherapy regimen outperformed chemotherapy alone, but cadonilimab plus chemotherapy delivered the largest survival gain, with a hazard ratio for overall survival of 0.62 (95 percent confidence interval 0.50 to 0.77), compared with hazard ratios of 0.75 to 0.82 for the five PD-(L)1 antibodies: sugemalimab, sintilimab, pembrolizumab, tislelizumab and nivolumab. In the indirect comparison against the pooled PD-(L)1 class, cadonilimab was associated with a statistically significant 22 percent reduction in the hazard of death (hazard ratio 0.78, 95 percent confidence interval 0.62 to 0.98), with essentially no heterogeneity among trials. Treatment ranking by P-score placed cadonilimab first with a probability score of 0.9586, well ahead of the rest of the field, and progression-free survival followed the same pattern, with a hazard ratio of 0.70 (95 percent confidence interval 0.57 to 0.86) favoring the bispecific approach.

The mechanistic rationale for this advantage lies in cadonilimab’s unusual tetravalent design. Gastric adenocarcinomas commonly express the immune checkpoints PD-1 and CTLA-4, which tumors exploit to suppress T-cell responses, and preclinical work has long shown that blocking both pathways synergistically enhances antitumor immunity. Conventional combination immunotherapy with separate PD-1 and CTLA-4 antibodies, tested in the CheckMate 649 trial, was hampered by dose-limiting toxicity and failed to improve survival. Cadonilimab instead packs both binding specificities into one antibody that preferentially accumulates in tumor tissue where PD-1 and CTLA-4 are co-expressed, concentrating dual blockade at the tumor site while sparing normal tissue. That design, the authors argue, explains both the improved efficacy and the tolerability profile observed in COMPASSION-15.

Safety data appear to support that interpretation. Across the included trials, no statistically significant differences emerged between cadonilimab and PD-(L)1 inhibitors in Grade 3 or higher treatment-related adverse events (odds ratio 0.83, 95 percent confidence interval 0.54 to 1.28) or serious adverse events (odds ratio 0.89, 95 percent confidence interval 0.56 to 1.42). Egger’s tests for publication bias were non-significant across all endpoints, and leave-one-out sensitivity analyses left the direction and significance of every primary result unchanged. Still, the authors caution that the confidence intervals around the safety comparisons are wide and rest on a limited number of trials, so a clinically meaningful difference in toxicity cannot be definitively excluded.

The most consequential findings emerge from exploratory subgroup analyses. In patients with low PD-L1 expression—combined positive scores below 10—the hazard ratio for overall survival favored cadonilimab over PD-(L)1 therapy with a point estimate of 0.77 (95 percent confidence interval 0.58 to 1.01), consistent across the CPS below 1 and below 5 cutoffs, while the single-target antibodies showed little or no benefit versus chemotherapy in the same strata. Even more pronounced was the liver metastasis subgroup, where cadonilimab reduced the hazard of death by 33 percent relative to PD-(L)1 inhibitors (hazard ratio 0.67, 95 percent confidence interval 0.49 to 0.93) and halved it relative to chemotherapy alone. This matters because liver metastases deplete peripheral T cells, erode intratumoral T-cell diversity and enrich immunosuppressive regulatory T cells and macrophages, creating a microenvironment that single-agent PD-1 blockade struggles to overcome; the authors propose that simultaneous CTLA-4 inhibition, which suppresses regulatory T cells, counters this biology more effectively. Statistically significant advantages for cadonilimab also appeared in male patients and those with an ECOG performance status of 1, subgroups in which androgen-receptor signaling and heightened systemic inflammation respectively promote T-cell exhaustion that dual checkpoint blockade may more fully reverse.

The authors are careful to frame these subgroup results as hypothesis-generating. All subgroup estimates derive from study-level aggregate data rather than individual patient information, which introduces the risk of ecological bias and limits control of within-trial confounding, and the PD-L1 analyses relied on different immunohistochemistry platforms, albeit assays with demonstrated substantial to excellent concordance in gastric cancer. Ranking analyses are sensitive to network structure and cannot by themselves establish superiority. Nevertheless, the overall picture is internally consistent: for patients whose tumors express high levels of PD-L1, all immunotherapy regimens deliver clear survival benefits over chemotherapy, but for the large populations left in clinical limbo—those with low PD-L1 expression, liver metastases, or intermediate expression where regulatory debate continues—this analysis suggests that a bispecific antibody harnessing two immune escape pathways simultaneously may be the preferable first-line partner for chemotherapy. The findings stop short of Level 1 evidence, and the authors call explicitly for prospective head-to-head trials, but they mark the first quantitative indication that bispecific checkpoint engineering could redraw the treatment algorithm for advanced gastric and gastroesophageal junction cancer.

Subject of Research: Indirect comparison of cadonilimab, a PD-1/CTLA-4 bispecific antibody, versus PD-(L)1 inhibitors as first-line therapy for advanced gastric and gastroesophageal junction cancer

Article Title: Survival Outcomes With Cadonilimab Versus PD‐(L)1 Therapy in Front‐Line Gastric Cancer: A Network Meta‐Analysis

Article References: Yu, Z.-K., Yi, J.-H., Xue, J., Huang, Y.-C., Zhao, Y., Jiang, C., Yin, C.-X., Xia, B., Zhou, Y.-X., He, W.-Z., & Xia, L.-P. (2026). Survival Outcomes With Cadonilimab Versus PD ‐(L)1 Therapy in Front‐Line Gastric Cancer: A Network Meta‐Analysis. Cancer Reports, 9(9), Article e70672. https://doi.org/10.1002/cnr2.70672

Image Credits: AI Generated

DOI: 10.1002/cnr2.70672

Keywords: cadonilimab, gastric cancer, gastroesophageal junction cancer, network meta-analysis, immune checkpoint inhibitors, PD-1, CTLA-4, bispecific antibody, PD-L1 expression, liver metastasis, overall survival, COMPASSION-15

The research integrates transcriptomic profiles and clinical data from over 1,500 gastric cancer patients spanning seven independent cohorts, creating a robust molecular classification system founded on glycogene expression patterns. This glycosylation-based molecular signature delineates distinct patient clusters associated with differential tumor stage, recurrence risk, and survival outcomes. Among the 12 critical glycogenes identified, GXYLT2 emerged as the most potent prognostic indicator, heralding its potential clinical utility.

Statistical analyses revealed a compelling correlation between elevated GXYLT2 expression and advanced tumor staging in gastric cancer, alongside significantly poorer overall survival and disease-free survival rates. Intriguingly, stratification by histological subtype demonstrates that GXYLT2 expression is markedly enriched in diffuse-type GC compared to the intestinal subtype, reinforcing the gene’s subtype-specific oncogenic relevance. Immunohistochemical staining substantiated these findings, showing strong GXYLT2 protein expression in diffuse gastric tumors, thus underscoring its viability as a translational biomarker.

Beyond correlative evidence, functional assays decisively illustrate that GXYLT2 actively promotes malignant phenotypes. Genetic silencing of GXYLT2 in diffuse-type gastric cancer cell lines led to a profound reduction in proliferative capacity, invasive potential, and sphere-forming ability—hallmarks of cancer aggressiveness and stemness. Conversely, overexpression experiments confirmed that while GXYLT2 alone is insufficient to induce oncogenic traits in intestinal-type GC models, its presence within the diffuse-type cellular context is essential to sustain malignancy, suggesting a context-dependent oncogenic network.

Mechanistically, this study elucidates the molecular pathway through which GXYLT2 exerts its oncogenic function. GXYLT2 was found to potentiate the Wnt/β-catenin signaling pathway, a critical regulator of cellular proliferation and differentiation frequently deregulated in cancers. Loss of GXYLT2 function boosts phosphorylation of β-catenin—a modification that targets the protein for degradation—thereby diminishing its nuclear accumulation and decreasing transcription of downstream Wnt-responsive genes pivotal for tumor progression.

A key intermediary in this regulatory cascade is protein phosphatase 2A (PP2A), whose activity is suppressed by GXYLT2. The inhibition of PP2A ensures sustained activation of β-catenin signaling, facilitating tumor growth and invasion. Notably, restoring PP2A activity following GXYLT2 knockdown effectively counteracted Wnt pathway hyperactivation, providing a mechanistic rationale for targeting this axis therapeutically in diffuse-type gastric cancer.

The translational relevance of these molecular insights was confirmed through rigorous in vivo experimentation. Xenograft models demonstrated that GXYLT2 silencing markedly curtailed tumor growth and cell proliferation within diffuse GC contexts, cementing the gene’s role as a driver of tumor aggressiveness and a viable candidate for targeted intervention. These preclinical findings pave the way for further development of GXYLT2-focused diagnostic tools and therapeutic strategies.

Collectively, this study establishes GXYLT2 as a bifunctional molecule integral to both the clinical prognosis and the biological underpinnings of diffuse-type gastric cancer. By harnessing large-scale cohort data and cutting-edge molecular biology techniques, the researchers have defined a glycosylation-centric classification system that enhances patient stratification and opens new therapeutic avenues. Targeting GXYLT2 or its downstream effectors in the Wnt/β-catenin pathway may revolutionize treatment paradigms and improve outcomes for patients afflicted by this aggressive cancer subtype.

The discovery of GXYLT2’s role underscores the broader significance of glycosylation modifications in cancer biology, an area that has historically been underexplored. Aberrant glycosylation can profoundly influence cell signaling, adhesion, and immune evasion—factors instrumental in tumor development and metastasis. This study’s glycosylation-focused molecular classification thus not only serves as a prognostic tool but also generates new hypotheses regarding the molecular drivers of gastric cancer heterogeneity.

Moreover, the context-dependent effects of GXYLT2 highlight the complexity of oncogenic networks within tumor subtypes. The inability of GXYLT2 overexpression to drive aggressiveness in intestinal-type GC suggests that co-occurring molecular alterations or specific cellular environments are requisite for its oncogenic activity. This finding advocates for precision medicine approaches that consider tumor subtype and molecular context when designing targeted therapies.

Future research may explore combinatorial strategies incorporating GXYLT2 inhibition with agents modulating Wnt signaling or PP2A activity, capitalizing on the mechanistic insights uncovered. Additionally, the glycosylation signature identified here may serve as a foundation for the development of novel biomarkers to aid early diagnosis, prognostication, and treatment monitoring in gastric cancer.

In summary, this meticulously conducted and translationally relevant investigation firmly positions GXYLT2 as a critical biomarker and effector in the pathogenesis of diffuse-type gastric cancer. Advancing our understanding of glycosylation-mediated regulation and Wnt/β-catenin signaling in malignancy could ultimately lead to more effective, personalized interventions, offering hope to patients battling this formidable disease.

Subject of Research: Molecular characterization and functional analysis of GXYLT2 in diffuse-type gastric cancer

Article Title: Identification of glycogene-based molecular classification and correlations between the expression levels of 12-glycogene signature and molecular features in GC patients

News Publication Date: Not specified

Web References:

• Genes & Diseases Journal
• DOI: 10.1016/j.gendis.2025.101673

Image Credits: Jiale Yang, Jiajun Wu, Ziqiang Chen, Xiangyun Hou, Xiaojing Li, Zhaorui Liu, Kai Yin, Tao Pang, Ruimin Huang, Jun Yan

Keywords: Gastric cancer, GXYLT2, glycosylation, Wnt/β-catenin signaling, diffuse-type gastric cancer, prognostic biomarker, tumor aggressiveness, molecular classification

Gastric cancer remains a formidable global health challenge. While early detection enables curative interventions, traditional surgical approaches, often involving gastrectomy, carry significant risks, including postoperative complications and long-term alterations in nutritional status. Young patients, in particular, face challenges that extend beyond survival, encompassing psychosocial factors and quality of life, which are critical considerations in treatment selection.

Endoscopic submucosal dissection, a minimally invasive endoscopic technique, allows for en bloc resection of early-stage tumors confined to the mucosa or superficial submucosa without lymph node metastasis. Its usage has been well studied in older patient cohorts, but until now, comprehensive data about its efficacy and safety in younger demographics were lacking.

This extensive multicenter retrospective analysis, encompassing patient data from January 2015 to December 2022, sheds light on the comparative outcomes of ESD versus traditional surgical approaches in patients 45 years or younger. The study scrutinized vital metrics such as overall survival (OS), disease-free survival (DFS), and the nuanced quality of life indices that are particularly consequential in a younger cohort.

Among 154 young patients included in the study, a subgroup of 41 underwent ESD while 113 received surgical treatment. Remarkably, the ESD cohort demonstrated an OS rate of 97.6% and a DFS rate of 97.6%, aligning closely with the surgery group’s OS and DFS rates of 99.1%. Statistical analysis confirmed that these differences were insignificant, effectively validating ESD’s oncologic safety and efficacy equivalence.

Further extending their inquiry, the investigators evaluated ESD outcomes across a larger cohort of 833 patients segmented into three age groups: ≤45 years, 46–65 years, and >65 years. The data revealed consistently high efficacy of ESD regardless of age, with DFS rates showing no statistical disparity, reinforcing the procedure’s reliability as a standard-of-care treatment for EGC.

One of the pivotal facets of this study was the comprehensive assessment of post-treatment quality of life. The authors observed that patients treated with ESD experienced significantly fewer gastrointestinal side effects such as nausea and diarrhea compared to their surgical counterparts. This finding is particularly consequential, as postoperative complications can severely impair daily functioning and recovery trajectories, especially for younger individuals with active lifestyles.

Additionally, the study highlighted that ESD patients maintained stable body weight and body mass index (BMI) following treatment, contrasting with surgery patients who suffered notable reductions in these parameters. Preservation of nutritional status is a critical metric, as weight loss and malnutrition can lead to diminished physical resilience and lowered immunity, potentially jeopardizing long-term outcomes.

The reduced morbidity associated with ESD usage aligns with the procedure’s minimally invasive nature, which avoids the extensive tissue disruption characteristic of traditional surgery. This advantage not only expedites recovery but also supports sustained physiological well-being—a consideration of heightened importance for younger patient populations with extended life expectancy.

Therapeutic decision-making in early gastric cancer traditionally prioritizes oncologic control, sometimes at the expense of the patient’s quality of life, especially when more invasive techniques are employed. This study challenges that paradigm by presenting robust evidence that ESD can offer an optimal balance, achieving both curative potential and superior life quality post-intervention.

Moreover, the implications of this research extend beyond individual patient outcomes. Adoption of ESD as a preferred approach in suitable young patients could yield systemic healthcare benefits, including reduced hospital stays, decreased healthcare expenditures, and minimized burden on surgical resources.

While the study’s retrospective design warrants cautious interpretation, its multicenter nature and comprehensive dataset provide a compelling foundation for future prospective randomized trials. These trials will be instrumental in further validating ESD’s role and refining patient selection criteria to maximize benefit.

Furthermore, advancements in endoscopic technology and operator expertise will likely enhance the safety profile and accessibility of ESD, potentially expanding its indication spectrum. Integration with emerging diagnostic modalities such as enhanced imaging and molecular profiling might further optimize personalized treatment strategies.

In clinical practice, these findings advocate for multidisciplinary evaluation of young EGC patients, incorporating gastroenterologists, surgical oncologists, pathologists, and nutritionists, to tailor treatment plans that amalgamate oncologic efficacy with holistic patient-centered care.

The study underlines a paradigm shift in managing early gastric cancer among young patients, highlighting ESD as a transformative approach that not only preserves life but also restores and maintains the quality of that life in the aftermath of treatment.

As the medical community continues to prioritize survivorship and long-term well-being, interventions like ESD exemplify the future of cancer care where innovation, precision, and empathy intersect to optimize patient outcomes.

In summary, this pivotal research elevates endoscopic submucosal dissection from a minimally invasive option to a frontline therapeutic strategy in young patients with early gastric cancer, promising a new era where curative success coexists with enhanced post-treatment quality of life.

Subject of Research: Early gastric cancer treatment efficacy and safety comparison between endoscopic submucosal dissection and surgical intervention in patients aged 45 years or younger.

Article Title: Endoscopic submucosal dissection: a safe alternative to surgical intervention for young patients under 45 years of age with early gastric cancer. ESD vs. surgery in young EGC patients.

Article References:
Safi, M.H., Hui, Z., Xiaoyong, W. et al. Endoscopic submucosal dissection: a safe alternative to surgical intervention for young patients under 45 years of age with early gastric cancer. ESD vs. surgery in young EGC patients. BMC Cancer (2025). https://doi.org/10.1186/s12885-025-15293-4

Image Credits: Scienmag.com

DOI: https://doi.org/10.1186/s12885-025-15293-4