Cadonilimab plus chemotherapy in PD-L1-low gastroesophageal cancer: a bispecific opportunity?

Gastric and gastroesophageal junction (GEJ) cancers account for approximately 1 million new cases and more than 600,000 cancer-related deaths per year, making them the fifth leading cause of cancer mortality worldwide (1-3). The global burden of gastric/GEJ cancer is expected to rise due to population aging, rising rates of obesity and gastroesophageal reflux disease, as well as the rising incidence of early-onset (aged <50 years) gastric cancer driven by autoimmune gastritis and by dietary and lifestyle risk factors leading to disruption of the gut microbiome (4,5). Unfortunately, one-third of patients with gastric/GEJ cancer present with advanced, metastatic disease, with 5-year overall survival (OS) rates <10% (5). Thus, there is an urgent need to optimize systemic treatment strategies to improve clinical outcomes.

The current management of locally advanced, unresectable or metastatic gastric/GEJ cancer is informed by upfront identification of key molecular biomarkers, including microsatellite instability (MSI), programmed death ligand 1 (PD-L1), human epidermal growth factor receptor 2 (HER2) and Claudin 18.2 (CLDN18.2), help guide targeted therapeutic interventions. For HER2-negative and PD-L1-positive or MSI-high tumors, treatment has evolved to include the addition of programmed death-1 (PD-1) immune checkpoint inhibitors (ICIs), such as nivolumab, pembrolizumab, or tislelizumab, to a cytotoxic chemotherapy backbone, typically a fluoropyrimidine [5-fluorouracil (5-FU) or capecitabine] and platinum (more commonly oxaliplatin) based regimen (6). The phase III, randomized CheckMate 649 trial demonstrated that the addition of nivolumab to FOLFOX or CAPOX chemotherapy versus chemotherapy alone led to significant improvements in median OS [14.4 vs. 11.1 months; hazard ratio (HR) 0.71; 98.4% confidence interval (CI): 0.59–0.86] and median progression-free survival (PFS) (7.7 vs. 6.6 months; HR 0.68; 98% CI: 0.56–0.81) in patients with a PD-L1 combined positive score (CPS) ≥5 (7). Although the study did indicate a significant improvement in OS in the overall population as well as the PD-L1 CPS ≥1 subgroup, this clinical outcome benefit was likely driven by the substantial proportion of patients—about 60%—who had a PD-L1 CPS of ≥5. In addition, KEYNOTE-859, another phase III trial randomizing patients with HER2-negative gastroesophageal cancer to pembrolizumab plus 5-FU/cisplatin or capecitabine/oxaliplatin chemotherapy versus chemotherapy alone, demonstrated a significant improvement in OS in all patients (12.9 vs. 11.5 months; HR 0.78; 95% CI: 0.70–0.87) (8). However, the study further confirmed a PD-L1-survival gradient effect, with a greater magnitude of survival benefit observed with PD-L1 CPS ≥10 (median OS 15.7 vs. 11.8 months; HR 0.65; 95% CI: 0.53–0.79) (8). Finally, the phase III RATIONALE-305 trial also showed that the addition of tislelizumab to fluoropyrimidine plus platinum chemotherapy significantly improved OS in patients with advanced gastroesophageal cancer in all patients (median OS 15.0 vs. 12.9 months; HR 0.80; 95% CI: 0.70–0.92), but again with greater benefit with PD-L1 tumor area positivity (TAP) score of ≥5% (median OS 17.2 vs. 12.6 months; HR 0.74; 95% CI: 0.59–0.94) (9).

Collectively, these studies led to US regulatory approval of these PD-1 ICIs in combination with chemotherapy in the frontline setting for advanced, metastatic gastroesophageal cancer. However, the overall benefit of immunotherapy plus chemotherapy in tumors with low PD-L1 expression has been questioned. Using the Kaplan-Meier subtraction method, Zhao et al. analyzed data of PD-L1 subgroups previously unreported by pivotal clinical trials investigating frontline PD-1 inhibitor plus chemotherapy combinations versus chemotherapy alone in advanced gastroesophageal cancers, including CheckMate 649, KEYNOTE-062 (10), and KEYNOTE-590 (11), and showed no significant differences in OS and PFS with the addition of ICIs in the low PD-L1 expression groups (PD-L1 CPS 1–4 in CheckMate 649; PD-L1 CPS 1–9 in KEYNOTE-062 and KEYNOTE-590) (12). Furthermore, a meta-analysis of phase III randomized trials by Al Ghnaimat and colleagues including CheckMate 649, KEYNOTE-859, ORIENT-16 and RATIONALE-305, which compared PD-1 inhibitor plus chemotherapy versus chemotherapy alone in treatment-naive advanced gastroesophageal cancers that were PD-L1 low/negative (CPS <1, <5 or TAP <5%), demonstrated no significant improvement in OS (HR 0.92; 95% CI: 0.81–1.03; P=0.16; I²=0%) or PFS (HR 0.84; 95% CI: 0.70–1.02; P=0.08; I²=47%) (13). Consequently, regulatory authorities have issued more specific recommendations regarding utilization of PD-1 inhibitors in this setting, with the Food and Drug Administration (FDA) Oncologic Drugs Advisory Committee in the United States voting to recommend against the use of PD-1 inhibitors in tumors with PD-L1 CPS <1 and the European Medicines Agency (EMA) restricting approval of nivolumab to tumors with PD-L1 CPS ≥5 (6,14). With the clinical benefit of PD-1 inhibitors plus chemotherapy called into question in patients with advanced, metastatic gastroesophageal cancers with low PD-L1 expression, ongoing research has sought to identify different treatment strategies to overcome these limitations. One possible approach may be to combine the effects of two ICIs by targeting both the PD-L1 and cytotoxic T lymphocyte antigen-4 (CTLA-4) pathways to both prime immune T-cell response and overcome T-cell exhaustion in order to sustain response (15). Although combined checkpoint blockade, with agents such as nivolumab and ipilimumab, has demonstrated benefit in other tumor types such as melanoma and renal cell carcinoma, similar success has not been observed in gastroesophageal cancers (16,17). The ATTRACTION-6 study recently reported no significant improvement in OS of first-line nivolumab and ipilimumab plus chemotherapy versus chemotherapy alone for patients with advanced HER2-negative gastric/GEJ cancer (median OS 15.7 vs. 15.8 months; HR 0.90; 95% CI: 0.74–1.09) in the overall population; however, a trend toward OS benefit in the nivolumab and ipilimumab arm was seen in tumors with PD-L1 CPS ≥5 (OS 18.4 vs. 15.3 months; HR 0.80; 95% CI: 0.60–1.07) though not statistically significant (18).

Cadonilimab, also known as AK104, is a tetravalent bispecific human immunoglobulin G subclass 1 (IgG1) antibody targeting PD-1 and CTLA-4 receptors (19). The phase III randomized COMPASSION-15 trial demonstrated that compared with chemotherapy in patients with locally advanced or metastatic gastric/GEJ cancer, cadonilimab plus chemotherapy significantly improved OS (14.1 vs. 11.1 months; HR 0.66; 95% CI: 0.54–0.81) and PFS (7.0 vs. 5.3 months; HR 0.53; 95% CI: 0.44–0.65) (20). As expected, the magnitude of OS benefit was greater in PD-L1 CPS ≥5 (15.3 vs. 10.9 months; HR 0.58; 95% CI: 0.41–0.82). However, pre-specified subgroup analysis also suggested survival benefit with cadonilimab in the CPS <5 subgroup (OS 13.7 vs. 11.4 months; HR 0.75; 95% CI: 0.56–1.00) and higher overall response rate (ORR) (62.4% vs. 43.5%) (20). Moreover, the safety profile was manageable with comparable rates of grade ≥3 treatment-related adverse events (TRAEs) in the cadonilimab arm compared with other trials of anti-PD-1 plus chemotherapy (~60%) (7-9). Cadonilimab plus chemotherapy has subsequently been approved in China as first-line treatment in patients with advanced or metastatic gastric/GEJ cancer regardless of PD-L1 expression (20,21). However, it remains unclear how cadonilimab plus chemotherapy directly compares with anti-PD-1 plus chemotherapy, the latter of which is the current standard of care in the Western population.

In this context, Zhao and colleagues performed a retrospective analysis using propensity score matching (PSM) of patients with advanced gastric/GEJ cancer to evaluate the effectiveness and safety of cadonilimab plus chemotherapy compared with PD-1 inhibitor plus chemotherapy in patients with low PD-L1 expression (CPS <5) (22). Patients who were treated between 2022 and 2024 at Zhejiang Cancer Hospital in China were included. The PD-1 inhibitors used included nivolumab, tislelizumab, or sintilimab. Chemotherapy regimens included oxaliplatin plus S-1 (SOX) as well as capecitabine or 5-FU plus oxaliplatin (XELOX or FOLFOX). A total of 73 patients were included, with 52 patients (26 in each arm) undergoing final analysis after PSM. The mean follow-up was 11 months. Compared with the PD-1 inhibitor group, the cadonilimab group demonstrated numerically higher ORR (73.3% vs. 57.1%; P=0.45), and significantly increased median PFS (9.3 vs. 5.8 months; HR 0.43; 95% CI: 0.23–0.80) and OS (14.3 vs. 10.3 months; HR 0.49; 95% CI: 0.26–0.93), comparable to historical data. OS subgroup analyses also showed benefit in older patients (≥65 years), and those without liver metastases, and those with peritoneal disease. In terms of safety, grade ≥3 TRAEs were increased in the cadonilimab (30.8%) vs. PD-1 inhibitor (15.4%) groups. All-grade immune-related adverse events (irAEs) were somewhat increased in the cadonilimab group (30.8%) versus the anti-PD-1 group (23.1%); however, grade ≥3 irAEs were similar across both groups (3.8%). These findings were generally consistent with the known safety profile of these ICIs, with no unexpected adverse events observed.

Therefore, in this retrospective real-world, propensity-matched analysis of patients with advanced gastric/GEJ cancer with PD-L1 CPS <5, frontline cadonilimab plus chemotherapy significantly improved survival outcomes compared with PD-1 inhibitor plus chemotherapy while maintaining an acceptable adverse effect profile. There are possible underlying mechanisms that may account for the efficacy of cadonilimab observed in the setting of low PD-L1 expression. CTLA-4 has been reported to be highly expressed in gastric cancer (23,24). In tumors with low PD-L1 expression, CTLA-4-mediated signaling may thus play a more prominent role. In addition, cadonilimab’s tetravalent bispecific design leads to greater binding avidity in high-density PD-1/CTLA-4 settings in the tumor microenvironment (TME) and can bridge cells expressing PD-1 and CTLA-4, leading to a greater accumulation of tumor-infiltrating lymphocytes in the TME (19,25). Cadonilimab’s bispecific binding may also overcome Treg expansion and promote greater effector T-cell activation while simultaneously mitigating T-cell exhaustion (26). Furthermore, its activity differs from single-agent CTLA-4 inhibitors such as ipilimumab, which appears to function more effectively in a background of higher tumor-infiltrating Treg cells, which may be less common with low PD-L1 expression (27).

Nevertheless, the study has certain limitations. This was a small, non-randomized, retrospective study and may be susceptible to selection bias. Although PSM may help match patient characteristics, there may still be unmeasured variables contributing to confounding (28). The study also involved a single center in China, which limits generalizability to a larger global population, and its small sample size poses limitations for statistical analyses. Future prospective studies comparing cadonilimab versus anti-PD-1 agents plus chemotherapy in advanced gastric/GEJ cancer to confirm efficacy in a more diverse, international population are needed. Despite these limitations, Zhao et al. provide real-world support regarding efficacy and safety of cadonilimab that aligns with the findings from the COMPASSION-15 trial, particularly noted in the PD-L1-low subgroup analysis. Cadonilimab therefore holds promise in potentially overcoming the challenges with low PD-L1 expression and immune evasion (19,20,22).

Cadonilimab is a novel immunotherapeutic agent that may overcome limitations of anti-PD-1 and anti-CTLA-4 checkpoint inhibitors such as nivolumab and ipilimumab (alone and in combination) and promote greater T-cell-mediated anti-tumor activity. Further prospective clinical trials are needed to confirm the clinical benefits of this mechanistic advantage over PD-1 inhibitors, particularly in PD-L1-low gastric/GEJ cancers in a large, diverse patient population. In addition, given advances in biomarker-directed therapy, including anti-HER2 and anti-CLDN18.2 treatments, further exploration of potential synergy of cadonilimab with these targeted agents is warranted to further optimize frontline strategies and continue to improve survival outcomes.

Acknowledgments

None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, Journal of Gastrointestinal Oncology. The article did not undergo external peer review.

Funding: None.

Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at https://jgo.amegroups.com/article/view/10.21037/jgo-2026-0692/coif). D.L. received honoraria for consulting for Exelixis, AstraZeneca, Incyte, and BeOne, all of which are unrelated to the content of this manuscript. The other author has no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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