Abstract
Background
Cadonilimab (AK104) is a first-in-class bispecific antibody targeting programmed cell death-1 (PD-1) and cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4). This study evaluated the effectiveness and safety of cadonilimab plus chemotherapy vs. PD-1 inhibitor plus chemotherapy as first-line treatment for advanced gastric/gastroesophageal junction (G/GEJ) cancer with programmed cell death-ligand 1 (PD-L1) combined positive score (CPS) <5.
Methods
Between August 2022 and August 2024, patients with PD-L1 CPS <5 G/GEJ cancer who received first-line cadonilimab plus chemotherapy (cadonilimab group) or PD-1 inhibitor plus chemotherapy (PD-1 inhibitor group) were included. After propensity score matching (PSM), the objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), overall survival (OS), and safety were analyzed.
Results
Fifty-two patients were analyzed after PSM (26 per group). At data cutoff (February 28, 2025), median follow-up was 11.0 months [95% confidence interval (CI): 8.3–15.3]. Compared with the PD-1 inhibitor group, cadonilimab group exhibited a numerically higher ORR (73.3% vs. 57.1%, P=0.45). In addition, the median PFS [9.3 vs. 5.8 months; hazard ratio (HR) =0.43; 95% CI: 0.23–0.80; P=0.006] and OS (14.3 vs. 10.3 months; HR =0.49; 95% CI: 0.26–0.93; P=0.03) were significantly longer in the cadonilimab group than in the PD-1 inhibitor group. The incidence of treatment-related adverse events (AEs) was comparable between the two groups, occurring in 92.3% of patients receiving cadonilimab plus chemotherapy and 100.0% of those receiving PD-1 inhibitor plus chemotherapy. Immune-related AEs occurred in 8 patients (30.8%) in the cadonilimab group and 6 patients (23.1%) in the PD-1 inhibitor group.
Conclusions
Compared to PD-1 inhibitor plus chemotherapy, cadonilimab plus chemotherapy significantly improved PFS and OS with a manageable safety profile in the first-line treatment of advanced G/GEJ cancer with PD-L1 CPS <5 in a real-world setting.
Keywords: Cadonilimab, programmed cell death-1 inhibitor (PD-1 inhibitor), chemotherapy, gastric/gastroesophageal junction cancer (G/GEJ cancer), programmed cell death-ligand 1 combined positive score <5 (PD-L1 CPS <5)
Highlight box.
Key findings
• Cadonilimab plus chemotherapy significantly improved progression-free survival and overall survival compared to programmed cell death-1 inhibitor plus chemotherapy in the first-line treatment of advanced gastric/gastroesophageal junction (G/GEJ) cancer with programmed cell death-ligand 1 (PD-L1) combined positive score (CPS) <5, with a manageable safety profile.
What is known and what is new?
• Immune checkpoint inhibitors combined with chemotherapy have become the standard of care for first-line treatment of human epidermal growth factor receptor 2-negative, unresectable locally advanced, or metastatic G/GEJ cancer, but their survival benefit is largely restricted to patients with high PD-L1 expression.
• G/GEJ cancer with PD-L1 CPS <5 could also benefit from cadonilimab plus chemotherapy first-line treatment.
What is the implication, and what should change now?
• Cadonilimab plus chemotherapy could be considered a potential therapeutic option for advanced G/GEJ cancer with PD-L1 CPS <5, warranting further study.
Introduction
Gastric/gastroesophageal junction (G/GEJ) cancer represents the fifth most frequently diagnosed malignancy globally and remains the fifth leading cause of cancer-related mortality, accounting for approximately 6.8% of the total cancer deaths in 2022 (1). The prognosis remains poor, primarily due to the late-stage diagnoses and suboptimal treatment efficacy (2).
The rapidly developing field of immune checkpoint inhibitors (ICIs) enriches the first-line standard combination therapy of gastric cancer (GC) (3). However, controversy remains regarding the association between programmed cell death-ligand 1 (PD-L1) status and clinical benefit of ICIs, with the survival advantage primarily observed in patients with high PD-L1 expression, while those with low PD-L1 expression derive limited benefit (4-6). Recently, emerging evidence indicates that dual programmed cell death-1 (PD-1)/cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) inhibition has demonstrated efficacy across several tumors, improving responses to single-agent ICI therapy, and is now the standard of care in malignant melanoma (7) and renal cell carcinoma (8). In addition, preclinical studies suggested that a combination of anti-CTLA-4 and anti-PD-1 antibodies could inhibit cell proliferation, migration, invasion, epithelial-mesenchymal transition, and induce apoptosis in GC cells through regulation of β-catenin, mitogen-activated protein kinase, and phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT) signal pathways (9). However, dual ICIs have shown limited efficacy and carry a higher incidence of safety concerns compared to single-agent ICIs in G/GEJ cancer (10). Therefore, there is a pressing need to explore novel approaches to enhance outcomes for these patients.
Cadonilimab, also known as AK104, is the world’s first tetravalent bispecific human immunoglobulin G subclass 1 (IgG1) antibody targeting the clinically validated receptors PD-1 and CTLA-4 (11). This fragment crystallizable (Fc)-engineered IgG1 scaffold is designed to prevent binding to Fc gamma receptors (FcγRs) and complement component 1q (C1q), effectively minimizing lymphocyte depletion and macrophage-mediated cytokine release, which are associated with immune-related adverse events (irAEs) and reduced immunotherapy efficacy, thereby enhancing its safety profile (12). Preclinical study has shown that cadonilimab binds to distinct cells expressing PD-1 and CTLA-4, and its enhanced antigen-binding avidity in the tumor microenvironment (TME) could facilitate increased accumulation of tumor-infiltrating lymphocytes within the TME (13). Clinically, the potent antitumor activity and manageable safety profile of AK104 have been confirmed across multiple tumor types, including G/GEJ cancer (14-17). Notably, the phase III COMPASSION-15 trial demonstrated that cadonilimab plus chemotherapy [oxaliplatin plus capecitabine (XELOX)] significantly improved median overall survival [OS; 14.1 vs. 11.1 months; hazard ratio (HR) =0.66; 95% confidence interval (CI): 0.54–0.81; P<0.001] compared to placebo plus chemotherapy in patients with G/GEJ (18). Besides, the prespecified subgroup analysis showed that the HR for OS (13.7 vs. 11.4 months; HR =0.75; 95% CI: 0.56–1.00) favored cadonilimab over placebo in patients with PD-L1 combined positive score (CPS) <5 (18). These results indicated that G/GEJ cancer with PD-L1 CPS <5 could also benefit from cadonilimab plus chemotherapy first-line treatment.
This study aimed to evaluate the effectiveness and safety of cadonilimab plus chemotherapy vs. PD-1 inhibitor plus chemotherapy as first-line treatment for advanced G/GEJ cancer with PD-L1 CPS <5 in a real-world setting. In addition, the study addresses unmet clinical needs and advances treatment strategies by exploring the therapeutic potential of cadonilimab plus chemotherapy in the treatment of advanced G/GEJ cancer. We present this article in accordance with the STROBE reporting checklist (available at https://jgo.amegroups.com/article/view/10.21037/jgo-2025-aw-866/rc).
Methods
Study design and patients
This retrospective study analyzed the medical data of patients with G/GEJ cancer at Zhejiang Cancer Hospital who received first-line cadonilimab plus chemotherapy (cadonilimab group) or PD-1 inhibitor plus chemotherapy (PD-1 inhibitor group) between August 2022 and August 2024. The study included patients who were histologically confirmed unresectable locally advanced or metastatic G/GEJ, had a PD-L1 CPS <5, and had not received prior systemic therapy. No additional restrictive inclusion criteria were applied.
The study was approved by the Medical Ethics Committee of Zhejiang Cancer Hospital (approval No. IRB-2024-972), and was conducted according to the principles of the Declaration of Helsinki and its subsequent amendments. Informed consent was waived by the ethics committee due to the retrospective nature of the study.
Treatment
In the cadonilimab group, patients received cadonilimab plus chemotherapy. Cadonilimab was administered intravenously at a dose of either 10 mg/kg every 3 weeks or 6 mg/kg every 2 weeks. Patients in the PD-1 inhibitor group were treated with tislelizumab, nivolumab, or sintilimab plus chemotherapy. Chemotherapy regimens, including S-1, oxaliplatin, and capecitabine (SOX), XELOX, or folinic acid, fluorouracil, and oxaliplatin (FOLFOX), were administered concurrently as recommended by the Chinese Society of Clinical Oncology (CSCO) guidelines for first-line treatment of G/GEJ cancer.
Data collection and outcomes
Information on the patient’s clinical data was obtained from the electronic medical record databases, including demographic and clinical characteristics, treatment information, clinical outcomes, and safety.
Efficacy outcomes included objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), and OS. The ORR was defined as the proportion of patients with target lesions who achieved complete response (CR) or partial response (PR). The DCR was defined as the proportion of patients with target lesions who achieved CR, PR, or stable disease (SD) as the best response. The PFS was defined as the time from the start of therapy to disease progression or death due to any cause, whichever occurred first. The OS was calculated from initiation of therapy until death from any cause or last follow-up. Tumor response was assessed according to the Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1). Safety was assessed by adverse events (AEs) according to the Common Terminology Criteria Adverse Events version 5.0 (CTCAE 5.0).
Statistical analysis
Propensity score matching (PSM) was performed utilizing the MatchIt package (version 4.7.0) between the two groups to mitigate potential confounding variables. The propensity score was calculated using a logistic regression model with the following variables: age, gender, Eastern Cooperative Oncology Group (ECOG) performance status, body mass index (BMI), liver metastasis, peritoneal metastasis, and PD-L1 CPS scores. The cadonilimab group was matched 1:1 ratio to the anti-PD-1 antibody group using a greedy matching algorithm, with a caliper width specified at 0.05 of the standard deviation of the logit of the propensity score.
Descriptive statistics included means with standard deviations or medians with minimum and maximum for continuous variables and counts and percentages for categorical variables. The demographic and clinical characteristics of patients, response rate, and safety were summarized using descriptive statistics. Survival data were estimated using the Kaplan-Meier method and expressed as median values with corresponding two-sided 95% CIs. Cox proportional hazards regression models were used to analyze the correlation of baseline clinical characteristics with the efficacy of cadonilimab plus chemotherapy. All statistical analyses were carried out using SPSS 25 and GrarphPad Prism 8.
Results
Patients and treatment
A total of 73 patients with G/GEJ cancer were included in this study, with 26 in the cadonilimab group and 47 in the PD-1 inhibitor group. The characteristics of the study population are summarized in Table 1. Following PSM, 52 patients with G/GEJ cancer were analyzed, with 26 in the cadonilimab group and 26 in the PD-1 inhibitor group. There was no significant difference in any included variables between the two groups after PSM [all P>0.05; standardized mean difference (SMD) ≤0.2; Table 1].
Table 1. Baseline demographic and clinical characteristics.
| Variables | Before PSM | After PSM | |||||||
|---|---|---|---|---|---|---|---|---|---|
| Cadonilimab group (n=26) | PD-1 inhibitor group (n=47) | P | SMD | Cadonilimab group (n=26) | PD-1 inhibitor group (n=26) | P | SMD | ||
| Age (years) | 55.9±10.4 | 59.0±11.0 | 0.23 | 0.29 | 55.9±10.4 | 57.50±12.0 | 0.60 | 0.14 | |
| <65 | 20 (76.9) | 33 (70.2) | 0.66 | −0.15 | 20 (76.9) | 20 (61.5) | >0.99 | 0.00 | |
| ≥65 | 6 (23.1) | 14 (29.8) | 0.66 | 0.15 | 6 (23.1) | 6 (38.5) | >0.99 | 0.00 | |
| Gender | 0.37 | 0.57 | |||||||
| Female | 15 (57.7) | 22 (46.8) | 0.34 | −0.22 | 15 (57.7) | 17 (65.4) | 0.75 | 0.16 | |
| Male | 11 (42.3) | 25 (53.2) | 0.34 | 0.22 | 11 (42.3) | 9 (34.6) | 0.75 | −0.16 | |
| ECOG | 0.95 | 0.43 | |||||||
| 0 | 7 (26.9) | 13 (27.7) | 0.66 | 0.02 | 7 (26.9) | 5 (19.2) | 0.52 | −0.20 | |
| 1–2 | 19 (73.9) | 34 (72.3) | 0.66 | −0.02 | 19 (73.1) | 21 (80.8) | 0.52 | 0.20 | |
| BMI (kg/m2) | 22.54±3.4 | 21.15±2.5 | 0.05 | −0.57 | 22.54±3.4 | 21.31±2.4 | 0.14 | −0.51 | |
| <20 | 6 (23.1) | 17 (36.2) | 0.37 | 0.27 | 6 (23.1) | 7 (26.9) | 0.76 | 0.09 | |
| ≥20 | 20 (76.9) | 30 (63.8) | 0.37 | −0.27 | 20 (76.9) | 19 (73.9) | 0.76 | −0.09 | |
| Liver metastases | 0.92 | 0.53 | |||||||
| Yes | 8 (30.8) | 15 (31.9) | 0.81 | 0.03 | 8 (30.8) | 6 (23.9) | 0.56 | −0.18 | |
| No | 18 (69.2) | 32 (68.1) | 0.81 | −0.03 | 18 (69.2) | 20 (76.9) | 0.56 | 0.18 | |
| Peritoneum metastases | 0.57 | >0.99 | |||||||
| Yes | 10 (38.5) | 15 (31.9) | 0.65 | −0.14 | 10 (38.5) | 10 (38.5) | >0.99 | 0.00 | |
| No | 16 (61.4) | 32 (68.1) | 0.65 | 0.14 | 16 (61.5) | 16 (61.5) | >0.99 | 0.00 | |
| PD-L1 expression | 0.61 | 0.78 | |||||||
| CPS <1 | 16 (61.5) | 26 (55.3) | 0.48 | −0.13 | 16 (61.5) | 15 (57.7) | 0.80 | −0.08 | |
| 1≤ CPS <5 | 10 (38.5) | 21 (44.7) | 0.48 | 0.13 | 10 (38.5) | 11 (42.3) | 0.80 | 0.08 | |
Data are expressed as n (%) or mean ± standard deviation. BMI, body mass index; CPS, combined positive score; ECOG, Eastern Cooperative Oncology Group; PD-1, programmed cell death-1; PD-L1, programmed death-ligand 1; PSM, propensity score matching; SMD, standardized mean difference.
The data cutoff occurred on February 28, 2025. Patients received a median of 7.4±3.6 cycles of cadonilimab and 5.6±3.0 cycles of PD-1 inhibitor. The median follow-up was 11.0 months (95% CI: 8.3–15.3).
Efficacy
Of the 22 patients (cadonilimab group, n=15; PD-1 inhibitor group, n=7) with target lesions, the ORR was 73.3% (95% CI: 43.0–94.0%) and 57.1% (95% CI: 22.2–85.2%) for cadonilimab and PD-1 inhibitor groups (P=0.45), respectively (Table 2). The DCR was 100.0% (95% CI: 80.4–100.0%) and 100.0% (95% CI: 59.1–100.0%), respectively (P>0.99, Table 2). The best changes in tumor size from baseline to the study closing date are shown in Figure 1.
Table 2. Best overall response after PSM.
| Tumor responses | Patients with target lesions | ||
|---|---|---|---|
| Cadonilimab group (n=15) | PD-1 inhibitor group (n=7) | P | |
| Best overall response | – | ||
| CR | 0 | 1 (14.3) | |
| PR | 11 (73.3) | 3 (42.9) | |
| SD | 4 (26.7) | 3 (42.9) | |
| Progressive disease | 0 | 0 | |
| ORR | 11 (73.3) | 4 (57.1) | 0.45 |
| 95% CI (%) | 43.0–94.0 | 22.2–85.2 | |
| DCR | 15 (100.0) | 7 (100.0) | >0.99 |
| 95% CI (%) | 80.4–100.0 | 59.1–100.0 | |
Data are expressed as n (%), unless otherwise stated. CI, confidence interval; CR, complete response; DCR, disease control rate; ORR, objective response rate; PD-1, programmed cell death-1; PR, partial response; PSM, propensity score matching; SD, stable disease.
Figure 1.
The best changes in tumor size from baseline to the study closing date in patients with target lesions. CPS, combined positive score; ECOG, Eastern Cooperative Oncology Group; PD-1, programmed cell death-1; PD-L1, programmed death-ligand 1.
At the data cut-off, the median PFS was 9.3 months (95% CI: 7.9–10.6) in the cadonilimab group and 5.8 months (95% CI: 5.0–6.7) in the PD-1 inhibitor group (HR =0.43; 95% CI: 0.23–0.80; P=0.006; Figure 2A), with 6-month PFS rates of 76.1% (95% CI: 54.4–88.5%) and 48.3% (95% CI: 28.0–65.9%), respectively. The median OS was 14.3 months (95% CI: 11.5–17.0) in the cadonilimab group and 10.3 months (95% CI: 8.7–11.8) in the PD-1 inhibitor group, with an HR of 0.49 (95% CI: 0.26–0.93; P=0.03; Figure 2B). The estimated rates of OS at 12 and 18 months were 68.1% (95% CI: 49.7–86.4%) and 33.2% (95% CI: 14.5–53.2%) in the cadonilimab group, and 23.1% (95% CI: 9.4–40.3%) and 14.4% (95% CI: 4.1–31.0%) in the PD-1 inhibitor group, respectively. Subgroup analysis based on patient characteristics revealed that the OS benefit of cadonilimab plus chemotherapy was observed in patients aged ≥65 years (HR =0.18; 95% CI: 0.04–0.92; P=0.02), had no liver metastases (HR =0.44; 95% CI: 0.19–0.99; P=0.04), and had peritoneum metastases (HR =0.32; 95% CI: 0.10–0.98; P=0.04; Figure 3).
Figure 2.
Kaplan-Meier curves. (A) Kaplan-Meier curves of PFS; (B) Kaplan-Meier curves of OS. CI, confidence interval; HR, hazard ratio; mo, months; No., number; OS, overall survival; PD-1, programmed cell death-1; PFS, progression-free survival.
Figure 3.
Forest plot of OS according to subgroup. BMI, body mass index; CI, confidence interval; ECOG, Eastern Cooperative Oncology Group; HR, hazard ratio; OS, overall survival; PD-1, programmed cell death-1; PS, performance status.
Safety
The overall safety profiles were comparable between the two groups (Table 3), with 92.3% (24/26) of patients in the cadonilimab group and 100.0% (26/26) of patients in the PD-1 inhibitor group reporting at least one AE (P=0.04). The most frequently observed AEs of any grade in the cadonilimab and PD-1 inhibitor groups were platelet count decreased (46.2% vs. 34.6%, P=0.43), neutrophil count decreased (46.2% vs. 30.8%, P=0.30), and anorexia (46.2% vs. 53.8%, P=0.62). Grade 3–4 AEs were reported in 8 (30.8%) patients in the cadonilimab group and 4 (15.4%) patients in the PD-1 inhibitor group, respectively (P=0.25), with platelet count decreased (11.5% vs. 3.8%, P=0.47) being the most common. No treatment-related death developed in either group.
Table 3. Adverse events.
| Adverse events | Cadonilimab group (n=26) | PD-1 inhibitor group (n=26) | P | |||||
|---|---|---|---|---|---|---|---|---|
| All grades | Grade ≥3 | All grades | Grade ≥3 | All grades | Grade 3–4 | |||
| Any adverse events | 24 (92.3) | 8 (30.8) | 26 (100.0) | 4 (15.4) | 0.048 | 0.25 | ||
| Platelet count decreased | 12 (46.2) | 3 (11.5) | 9 (34.6) | 1 (3.8) | 0.43 | 0.47 | ||
| Neutrophil count decreased | 12 (46.2) | 3 (11.5) | 8 (30.8) | 0 | 0.31 | 0.19 | ||
| Anorexia | 12 (46.2) | 0 | 14 (53.8) | 0 | 0.63 | >0.99 | ||
| Aspartate aminotransferase increased ncreased | 10 (38.5) | 0 | 11 (42.3) | 0 | 0.84 | >0.99 | ||
| Asthenia | 9 (34.6) | 0 | 12 (46.2) | 0 | 0.43 | >0.99 | ||
| White blood cell count decreased | 9 (34.6) | 0 | 8 (30.8) | 0 | 0.81 | >0.99 | ||
| Nausea and vomiting | 9 (34.6) | 0 | 9 (34.6) | 0 | >0.99 | >0.99 | ||
| Alanine aminotransferase increased | 8 (30.8) | 0 | 10 (38.5) | 0 | 0.57 | >0.99 | ||
| Anemia | 6 (23.1) | 0 | 12 (46.2) | 1 (3.8) | 0.09 | 0.84 | ||
| Hyperthyroidism | 5 (19.2) | 0 | 5 (19.2) | 0 | >0.99 | >0.99 | ||
| Hyperbilirubinemia | 5 (19.2) | 0 | 5 (19.2) | 0 | >0.99 | >0.99 | ||
| Elevated creatinine | 4 (15.4) | 1 (3.8) | 1 (3.8) | 0 | 0.36 | 0.77 | ||
| Hypoalbuminemia | 2 (7.7) | 0 | 6 (23.1) | 0 | 0.12 | >0.99 | ||
| Rash | 2 (7.7) | 0 | 2 (7.7) | 0 | >0.99 | >0.99 | ||
| Ileus | 2 (7.7) | 0 | 1 (3.8) | 0 | >0.99 | >0.99 | ||
| Pyrexia | 2 (7.7) | 0 | 3 (11.5) | 0 | >0.99 | >0.99 | ||
| Renal failure | 1 (3.8) | 0 | 0 | 0 | >0.99 | >0.99 | ||
| Interstitial pneumonia | 1 (3.8) | 1 (3.8) | 0 | 0 | >0.99 | 0.77 | ||
| Diabetes | 1 (3.8) | 0 | 0 | 0 | >0.99 | >0.99 | ||
| Proteinuria | 0 | 0 | 4 (15.4) | 0 | 0.047 | >0.99 | ||
| Hypothyroidism | 0 | 0 | 2 (7.7) | 1 (3.8) | 0.49 | 0.84 | ||
| Peripheral neurotoxicity | 0 | 0 | 2 (7.7) | 0 | 0.49 | >0.99 | ||
| Autoimmune myocarditis | 0 | 0 | 1 (3.8) | 1 (3.8) | >0.99 | >0.99 | ||
| irAEs | 8 (30.8) | 1 (3.8) | 6 (23.1) | 1 (3.8) | 0.56 | >0.99 | ||
| Hyperthyroidism | 5 (19.2) | 0 | 5 (19.2) | 0 | >0.99 | >0.99 | ||
| Rash | 2 (7.7) | 0 | 2 (7.7) | 0 | >0.99 | >0.99 | ||
| Interstitial pneumonia | 1 (3.8) | 1 (3.8) | 0 | 0 | 0.37 | 0.77 | ||
| Hypothyroidism | 0 | 0 | 2 (7.7) | 0 | 0.49 | >0.99 | ||
| Autoimmune myocarditis | 0 | 0 | 1 (3.8) | 1 (3.8) | 0.30 | 0.84 | ||
Data are expressed as n (%). irAE, immune-related adverse event; PD-1, programmed cell death-1.
AEs leading to discontinuation were reported in 2 (7.7%) patients in the cadonilimab group and 2 (7.7%) patients in the PD-1 inhibitor group. In the cadonilimab group, 8 (30.8%) patients experienced immune-related AEs, compared with 6 (23.1%) patients in the PD-1 inhibitor group (P=0.55; Table 3). The most common immune-related AE was hyperbilirubinemia, occurring in 19.2% of patients in each group (P>0.99). There was no statistically significant difference in immune-related AEs between the two groups (all grades, P=0.55; grade ≥3, P>0.99).
Discussion
This retrospective study summarized data on the effectiveness and safety of cadonilimab plus chemotherapy vs. PD-1 inhibitor plus chemotherapy as first-line treatment for advanced G/GEJ cancer with PD-L1 CPS <5 in a real-world setting. Cadonilimab plus chemotherapy demonstrated a numerically higher ORR compared to PD-1 inhibitor plus chemotherapy (73.3% vs. 57.1%), indicating a more promising antitumor activity. Importantly, this translated into meaningful survival benefits, with cadonilimab plus chemotherapy significantly extending both PFS (median: 9.3 vs. 5.8 months; HR =0.43; 95% CI: 0.23–0.80; P=0.006) and OS (median: 14.3 vs. 10.3 months; HR =0.49; 95% CI: 0.26–0.93; P=0.03) in patients with PD-L1 CPS <5 advanced G/GEJ cancer within a real-world clinical setting.
Currently, PD-1 inhibitor plus chemotherapy has become the standard of care for first-line treatment of human epidermal growth factor receptor 2 (HER2)-negative, unresectable locally advanced, or metastatic G/GEJ cancer (19). Although the combination of PD-1 inhibitor and chemotherapy improves outcomes, a pooled analysis from PD-L1 CPS subgroups in three pivotal phase III trials (CheckMate-649, KEYNOTE-062, and KEYNOTE-590) suggested that patients with low PD-L1 expression (CPS 1–4 and CPS 1–9) did not benefit from adding ICIs to chemotherapy (5). Additionally, the Food and Drug Administration’s Oncologic Drugs Advisory Committee has noted that the risk-benefit profile of PD-(L)1 as first-line therapy remains uncertain in HER2-negative G/GEJ cancer patients with PD-L1 expression below 10% based on CheckMate-649, KEYNOTE-859, and RATIONALE-305 studies. In contrast, although cadonilimab plus chemotherapy demonstrated a median OS (15.3 vs. 14.4–18.4 months) comparable to historical data for PD-1 inhibitor plus chemotherapy in advanced G/GEJ cancer with PD-L1 CPS ≥5, it appeared to confer additional clinical benefit in patients with PD-L1 CPS <5 (18,20,21). Similarly, in our study, cadonilimab plus chemotherapy showed better OS benefit in low PD-L1 populations compared to placebo plus chemotherapy (median OS, 13.7 vs. 11.4 months; HR =0.75), along with a higher ORR of 62.4% vs. 43.5%. The observed benefit of cadonilimab in low PD-L1 tumors might be related to differences in immune evasion mechanisms. CTLA-4, primarily expressed on T cells, binds to CD80/CD86 and blocks the stimulatory signaling required for T cell proliferation, which is normally mediated by CD28 binding to CD80/CD86 during the priming phase (22). In contrast, immune evasion via the PD-1/PD-L1 axis is mainly driven by overexpression of PD-L1 on cancer cells, which binds to PD-1 on antigen-stimulated T cells and inhibits the PI3K/AKT and rat sarcoma (Ras)/mitogen-activated protein kinase kinase (MEK)/extracellular signal-regulated kinase (ERK) signaling pathways (22). In tumors with low PD-L1 expression, CTLA-4-mediated pathways might play a more prominent role than PD-1 signaling (18). Dual blockade of PD-1 and CTLA-4 could therefore provide stronger immune activation than PD-1 inhibition alone, and chemotherapy might further enhance this effect by promoting tumor antigen release and altering the TME (23,24). Taken together, these data suggested that patients with low PD-L1 expression might benefit from immunotherapeutic strategies beyond PD-1 blockade alone. Although our real-world findings support the potential role of cadonilimab in this setting, prospective trials are needed to validate efficacy and identify optimal candidates for this approach.
The safety profile of cadonilimab plus chemotherapy or PD-1 inhibitor plus chemotherapy in our study was generally consistent with the established safety profiles (18,21,25,26), with no unexpected AEs. Between the two groups, the overall safety profiles were comparable (all grades, P=0.04; grade ≥3, P=0.25). Platelet count decreased (46.2% vs. 34.6%, P=0.43), neutrophil count decreased (46.2% vs. 30.8%, P=0.30), and anorexia (46.2% vs. 53.8%, P=0.62) were the most frequently observed AEs of any grade in the two groups. These AEs were generally mild, tolerable, and reversible. In addition, there was no statistically significant difference in immune-related AEs between the two groups (all grades, P=0.55; grade ≥3, P>0.99). Although the incidence of grade 3–4 AEs was higher in the cadonilimab group (30.8%) compared with the PD-1 inhibitor group (15.4%; P=0.25), it was notably lower than the rate reported for nivolumab plus ipilimumab combined with chemotherapy (88%) in the AIO-STO-O417 study (27). This might be attributable to the distinct molecular design of cadonilimab, specifically its Fc-null configuration, which was engineered to attenuate antibody-dependent cellular cytotoxicity and might consequently reduce the incidence of immune-mediated toxicities in clinical settings (13).
Several limitations of our study should be acknowledged. Firstly, its retrospective design might cause selection bias and could have led to suboptimal completeness and timeliness in AE reporting. Secondly, the relatively small sample size, particularly in subgroup analyses, might have limited the statistical power and potentially affected the results’ reliability. Thirdly, although PSM was used to control for confounding factors, eliminating all potential confounders remains challenging, necessitating cautious interpretation of some results. Despite these limitations, the findings of our study were consistent with that of the COMPASSION-15 trial (18), providing valuable real-world information about cadonilimab plus chemotherapy as first-line treatment for advanced G/GEJ cancer with PD-L1 CPS <5.
Conclusions
In summary, this study showed that cadonilimab plus chemotherapy significantly improved PFS and OS compared to PD-1 inhibitor plus chemotherapy in the first-line treatment of advanced G/GEJ cancer with PD-L1 CPS <5. The safety profile of this combination was manageable and comparable to that of PD-1 inhibitor plus chemotherapy. These findings indicate that cadonilimab plus chemotherapy could be considered a potential therapeutic option for this population, warranting further study.
Supplementary
The article’s supplementary files as
Acknowledgments
We are grateful to Akeso Biopharma Inc. for supplying cadonilimab for this study. In addition, a preliminary analysis of the data was presented as an abstract at the European Society for Medical Oncology (ESMO) Congress 2023 (Ann Oncol 2023;34:Abstract #194P).
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. The study was approved by the Medical Ethics Committee of Zhejiang Cancer Hospital (approval No. IRB-2024-972), and was conducted according to the principles of the Declaration of Helsinki and its subsequent amendments. Informed consent was waived by the ethics committee due to the retrospective nature of the study.
Footnotes
Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://jgo.amegroups.com/article/view/10.21037/jgo-2025-aw-866/rc
Funding: This work was supported by the East Clinical Center of Oncology (No. ECCO-KY-23003).
Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jgo.amegroups.com/article/view/10.21037/jgo-2025-aw-866/coif). All authors report that Akeso Biopharma Inc. supplied cadonilimab for this study, and this work was supported by the East Clinical Center of Oncology (No. ECCO-KY-23003). The authors have no other conflicts of interest to declare.
Data Sharing Statement
Available at https://jgo.amegroups.com/article/view/10.21037/jgo-2025-aw-866/dss
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