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

Gastric cancer and cancer arising at the junction between the esophagus and stomach remain difficult to treat when they have spread beyond the site where they began. In advanced disease, surgery is often no longer sufficient, and systemic therapy becomes the central approach. Chemotherapy can damage rapidly dividing tumor cells, but its effects may be limited by resistance, tumor heterogeneity and the ability of malignant cells to adapt. At the same time, tumors can manipulate their surrounding tissue to create an environment that suppresses immune responses and supplies the growing mass with new blood vessels. The SBAGA study is based on the idea that interrupting several of these processes simultaneously could produce a more durable therapeutic effect than targeting any single mechanism.

Sintilimab is a monoclonal antibody designed to block programmed cell death protein 1, or PD-1, an immune checkpoint found on the surface of T cells. Under normal conditions, the PD-1 pathway helps prevent excessive immune activation and protects healthy tissues from immune attack. Many cancers exploit this regulatory system by using PD-1-related signaling to weaken T-cell activity against tumor cells. By preventing the interaction that suppresses T cells, sintilimab may help restore part of the immune system’s ability to recognize and attack malignant cells. This does not mean that every tumor will respond: immune activation depends on factors such as tumor biology, antigen presentation, the condition of the surrounding immune cells and the presence of other suppressive signals.

IBI305 contributes a second targeted mechanism. It is a biosimilar of bevacizumab, an antibody that binds vascular endothelial growth factor, or VEGF. VEGF is a major signal that encourages the formation of new blood vessels, a process known as angiogenesis. Tumors often require an expanded blood supply to obtain oxygen and nutrients as they grow, and VEGF can help establish that supply. Blocking VEGF may restrict tumor vascular development and can also alter the abnormal structure of tumor blood vessels. In theory, this vascular remodeling may make it easier for immune cells and anticancer drugs to enter tumor tissue. The combination therefore seeks not only to starve the tumor of support but also to make its local environment less hostile to immune attack.

The use of a biosimilar is an important practical feature of the trial. Biosimilars are biological medicines developed to be highly similar to an already approved reference product, with no clinically meaningful differences expected in quality, safety or effectiveness for their authorized uses. Unlike simple chemical drugs, biological medicines are produced in living systems and cannot be copied molecule-for-molecule in the same way as conventional generics. Their development requires analytical comparisons and clinical or pharmacological evidence showing that the biosimilar performs as expected. If IBI305 can provide comparable anti-VEGF activity at a lower cost or with improved availability, it could influence how combination treatment is delivered, particularly in health systems where access to expensive biologic medicines remains uneven.

Chemotherapy forms the third component of the SBAGA regimen. Although newer therapies have transformed cancer care, cytotoxic drugs continue to play a major role in advanced gastric cancer because they can act rapidly against dividing cells and may affect tumor populations that are less responsive to immune or vascular therapies. Chemotherapy can also release tumor antigens as cancer cells die, potentially giving the immune system additional material to recognize. At the same time, it can suppress immune cells and cause substantial side effects, making dose selection and treatment scheduling critical. The phase Ib portion of a study is commonly used to evaluate tolerability, identify dose-limiting toxicities and establish a practical regimen for later testing, while the phase II portion generally explores preliminary antitumor activity in a larger group.

The single-arm design means that participants receive the investigational combination without being randomly assigned to a comparison group within the study. This approach can be efficient when researchers are seeking an early signal of benefit or determining whether a treatment is suitable for a larger randomized trial. It also creates important interpretive limits. Without a concurrent control group, it is difficult to determine how much of an observed effect comes from the new combination rather than from patient selection, changes in supportive care or the expected performance of existing treatments. Historical comparisons can provide context, but they are vulnerable to differences in disease stage, biomarker status, previous treatment practices and methods of assessing response. The findings should therefore be viewed as evidence-generating rather than definitive proof that the regimen is superior to standard care.

The biological logic of the combination is compelling but also complex. Immune checkpoint blockade can cause inflammatory complications when activated T cells attack normal organs, while VEGF inhibition may contribute to hypertension, bleeding, impaired wound healing, blood-clotting events or kidney-related problems. Chemotherapy adds risks such as fatigue, nausea, reduced blood-cell counts, infection and damage to rapidly renewing tissues. When these treatments are used together, side effects may overlap or interact, and clinicians must distinguish treatment-related inflammation from symptoms caused by cancer or infection. Careful monitoring of blood pressure, blood counts, organ function and immune-related symptoms is therefore central to evaluating whether the strategy is clinically manageable.

Another question concerns which patients are most likely to benefit. Advanced gastric and gastroesophageal junction adenocarcinomas are not biologically uniform diseases. Tumors can differ in their immune-cell content, PD-L1 expression, DNA repair features, genetic alterations, vascular behavior and sensitivity to chemotherapy. A treatment that works well in one molecular or immunological subgroup may be less effective in another. The SBAGA study may help researchers understand whether clinical outcomes are associated with measurable biomarkers, although the citation alone does not provide the trial’s numerical results, response rates, survival data or subgroup analyses. Those details will be essential for determining whether the regimen should move toward randomized comparison and for identifying the patients in whom its risks are justified.

The study arrives at a time when cancer therapy is increasingly organized around combinations designed to reshape the tumor microenvironment. The central challenge is not simply to kill cancer cells, but to overcome the protective ecosystem that tumors build around themselves. By pairing PD-1 blockade with VEGF inhibition and chemotherapy, the researchers are testing whether immune activation, vascular modulation and direct cytotoxic treatment can reinforce one another. The importance of the report will ultimately depend on the full clinical data, including treatment exposure, adverse events, objective tumor responses, progression-free survival and overall survival. For now, the phase Ib/II investigation represents a carefully structured attempt to evaluate whether a biosimilar-based immunotherapy combination can expand treatment options for patients facing advanced gastric or gastroesophageal junction cancer.

Subject of Research: First-line combination treatment for advanced gastric or gastroesophageal junction adenocarcinoma using sintilimab, the bevacizumab biosimilar IBI305 and chemotherapy.

Article Title: Sintilimab plus Bevacizumab biosimilar IBI305 and chemotherapy as a first-line treatment in advanced gastric or gastroesophageal junction adenocarcinoma (SBAGA): a single-arm, phase Ib/II study.

Article References: Cheng, M., Zhang, P., Hu, Q. et al. “Sintilimab plus Bevacizumab biosimilar IBI305 and chemotherapy as a first-line treatment in advanced gastric or gastroesophageal junction adenocarcinoma (SBAGA): a single-arm, phase Ib/II study.” Nature Communications (2026). https://doi.org/10.1038/s41467-026-76502-7

Image Credits: AI Generated

DOI: 10.1038/s41467-026-76502-7

Keywords: gastric cancer, gastroesophageal junction adenocarcinoma, sintilimab, IBI305, bevacizumab biosimilar, immunotherapy, chemotherapy, angiogenesis, PD-1, phase Ib/II clinical trial

Gastric cancer remains the fifth most frequently diagnosed malignancy worldwide and ranks fourth in its contribution to cancer-related deaths, underscoring the dire need for innovative interventions. Immunotherapy has heralded new hope in various cancers by harnessing the immune system to recognize and destroy malignant cells. However, the heterogeneous nature of the TME in gastric cancer poses significant challenges, often dampening immune responses and limiting therapeutic outcomes. Understanding the molecular underpinnings that shape this environment is crucial, and CD2AP has now been thrust into the spotlight as a key regulator.

CD2AP is traditionally known for its role in cytoskeletal organization and cell signaling, but its involvement in cancer immunology remained ambiguous until now. Utilizing comprehensive RNA sequencing data from The Cancer Genome Atlas (TCGA), the research team conducted a pan-cancer analysis, meticulously profiling CD2AP expression across multiple malignancies. Remarkably, CD2AP expression was found upregulated within the stromal compartments of various tumors, hinting at a conserved role in TME architecture and immune modulation.

Focusing specifically on stomach adenocarcinoma, the researchers employed robust bioinformatics pipelines to dissect the association between CD2AP levels and critical immunological features. These included the elaborate cancer immunity cycle stages, expression patterns of immune checkpoint molecules, immunomodulatory factors, and the prevalence of tumor-infiltrating immune cells (TIICs). This multi-dimensional analysis illuminated how CD2AP correlates with a ‘stromal reduced’ TME—a microenvironment characterized by diminished stromal content but potentially heightened immune cell activity.

This ‘stromal reduced’ milieu correlated positively with enhanced immunotherapy responsiveness, positioning CD2AP not merely as a bystander but as an active contributor to shaping the immune contexture that favors therapeutic success. Patients exhibiting elevated CD2AP expression concurrently showed increased markers such as CD4, CD20, and CD57, each reflecting pivotal immune subsets including helper T cells, B cells, and natural killer cells respectively. This triad of high immune marker expression combined with CD2AP abundance was associated with improved prognosis and survival outcomes.

To translate these findings into clinical utility, the study ventured into prognostic modeling by constructing an immune-related risk score (IRS) that integrates CD2AP expression with other immune parameters. The IRS demonstrated robust predictive capability for patient outcomes in STAD, potentially guiding personalized medicine approaches. This score empowers oncologists to stratify patients according to their immunological and molecular tumor profiles, refining treatment strategies to maximize immunotherapeutic efficacy.

The molecular mechanisms by which CD2AP influences the stromal composition and immune cell infiltration within the TME are of particular interest. Although fully elucidating this requires further investigation, initial data suggest CD2AP modulates signaling pathways that regulate stromal cell activation and extracellular matrix deposition. By limiting excessive stromal expansion, CD2AP helps create a microenvironment that permits better immune cell penetration and function, a prerequisite for effective immune-mediated tumor eradication.

Moreover, CD2AP’s interplay with immune checkpoints and immunomodulators hints at a regulatory nexus where it could modulate the delicate balance between immune tolerance and activation within the tumor. This balance is critical for immunotherapy success, as immune evasion remains a hallmark of gastric cancer. Targeting CD2AP-related pathways could, therefore, synergize with existing checkpoint inhibitors, offering a combinatorial therapeutic strategy that enhances antitumor immunity while overcoming resistance mechanisms.

This research also spotlights the heterogeneity within gastric tumors, which often confounds treatment responses. By characterizing the tumor’s stromal and immune architecture through the lens of CD2AP expression, the study provides a refined understanding of tumor biology. It underscores the importance of considering the spatial and molecular context of tumors, which may explain why some patients respond remarkably well to immunotherapy while others do not.

Beyond its prognostic and therapeutic implications, CD2AP emerges as a promising biomarker for gastric cancer, aiding in early diagnosis, risk assessment, and monitoring treatment response. Biomarkers that reflect both tumor intrinsic features and the surrounding immune milieu are invaluable, as they offer a holistic view of disease state and progression. Incorporating CD2AP measurement into routine clinical workflows could transform patient management paradigms.

It is important to note that while the study leans heavily on bioinformatic analyses using large genomic datasets, subsequent experimental validations and clinical trials are warranted to fully establish CD2AP’s role and therapeutic potential. Investigations into its functional mechanisms at the cellular and molecular levels will unravel how modulating CD2AP expression influences TME remodeling and immune activation in vivo.

The broader implications of these findings extend beyond gastric cancer. Given CD2AP’s conserved expression patterns and its involvement in the immune microenvironment of multiple cancer types, it could represent a universal target for enhancing immunotherapy across malignancies. This opens exciting possibilities for cross-cancer therapeutic strategies leveraging CD2AP modulation.

In conclusion, the identification of CD2AP as a modulator of the stromal reduced tumor microenvironment and as a facilitator of immunotherapy response marks a significant advancement in gastric cancer research. This discovery not only enriches our molecular understanding of tumor-immune interactions but also paves the way for novel diagnostic and therapeutic innovations aimed at improving patient outcomes in this devastating disease.

As the oncology community eagerly anticipates further developments, the integration of CD2AP-related molecular insights into clinical practice holds the promise of transforming how gastric cancer is diagnosed, treated, and ultimately conquered.

Subject of Research: Gastric cancer tumor microenvironment and immunotherapy modulation via CD2AP

Article Title: CD2AP shapes a stromal reduced tumor microenvironment and contributes to immunotherapy in gastric cancer

Article References:
Li, H., Chen, H., Zhao, T. et al. CD2AP shapes a stromal reduced tumor microenvironment and contributes to immunotherapy in gastric cancer. BMC Cancer 25, 910 (2025). https://doi.org/10.1186/s12885-025-14248-z

Image Credits: Scienmag.com

DOI: https://doi.org/10.1186/s12885-025-14248-z