A phase Ib/II study of AK104, a PD-1/CTLA-4 bispecific antibody, combined with mXELOX as first-line therapy for advanced gastric or gastroesophageal junction (GEJ) adenocarcinoma

Ji, J.; Shen, Limei; Li, Z.; Gao, Xuan; Gong, Jun; Liu, D.; Wu, Xuming; Xu, Shuning; Xu, Jin; Li, B.; Wang, M.; Xia, Yu

doi:10.1093/annonc/mdz247.166

Annals of Oncology

2019

DOI: 10.1093/annonc/mdz247.166

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A phase Ib/II study of AK104, a PD-1/CTLA-4 bispecific antibody, combined with mXELOX as first-line therapy for advanced gastric or gastroesophageal junction (GEJ) adenocarcinoma

J. Ji¹,

Limei Shen²,

Z. Li³

et al.

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“…3 Furthermore, combination therapy with CTLA-4 plus PD-1 blockers was shown to significantly enhance efficacy and response, and is under investigation in advanced gastric or gastroesophageal junction adenocarcinoma. 4 To date, parameters such as the elevated expression of IC proteins, mismatch repair (MMR) deficiency and microsatellite instability (MSI) are some factors emerging as potential predictive biomarkers. 5,6 Nevertheless, MSI status and PD-L1 expression have been related to non-benefit of platinum-based chemotherapy (CMT) in adjuvant setting.…”

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confidence: 99%

Cytotoxic T‐lymphocyte‐associated protein 4 in gastric cancer: Prognosis and association with PD‐L1 expression

Pereira

Castria

Ramos

et al. 2021

Journal of Surgical Oncology

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Background: Cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) is one of the most studied immune checkpoint in gastric cancer (GC). However, the prognostic role of CTLA-4 expression in GC is poorly described. This study aimed to evaluate CTLA-4 expression in GC and its impact on survival, including patients treated with standard platinum-based chemotherapy (CMT), and association with PD-L1 expression.Methods: All GC patients who underwent D2-gastrectomy were investigated retrospectively. Tumor samples were examined for CTLA-4 and PD-L1 by immunohistochemistry. Tumor-infiltrating inflammatory cells, including CD4 + and CD8 + , were also examined.Results: Among the 284 GC patients included, 159 (56%) were CTLA-4 positive and the remaining 125 (44%) were classified as negative. CTLA-4 positive GC was associated with increased inflammatory cell infiltration (p < 0.001), high CD8 + T cells (p = 0.016) and PD-L1 expression (p = 0.026). Considering GC referred for treatment, CTLA-4 negative patients who received CMT had a significant improvement in disease-free survival compared to untreated CLTA-4 negative (p = 0.028). In multivariate analysis, GC positive for both CTLA-4 and PD-L1 had a prognostic impact on survival.Conclusion: CTLA-4 positive was associated with PD-L1 expression and a high tumor-infiltrating CD8 + T cells. Accordingly, positivity for both CTLA-4 and PD-L1 was an independent factor associated to better survival in GC patients. K E Y W O R D S chemotherapy, cytotoxic T-lymphocyte associated protein 4, gastric adenocarcinoma, gastric cancer, immune checkpoint 1 | INTRODUCTION Gastric cancer (GC) is one of the most common causes of cancer-related mortality worldwide. Despite recent advances in treatment, the prognosis of patients with advanced GC remains poor. 1 Therefore, the need to unveil novel biomarkers relate to survival and to better select patients who might benefit from evaluable therapies are required. It has been widely demonstrated that immunosuppressive microenvironment is related to GC progression and T-cell exhaustion is characterized by elevated expression of immune checkpoint (IC) proteins. 2

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mentioning

confidence: 99%

Cytotoxic T‐lymphocyte‐associated protein 4 in gastric cancer: Prognosis and association with PD‐L1 expression

Pereira

Castria

Ramos

et al. 2021

Journal of Surgical Oncology

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Current status of immunotherapy in gastric cancer

Ji,

2023

Holist Integ Oncol

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Gastric cancer is one of the most common cancer with high mortality and morbilidity in East Asia, especially in China. In recent year, new treatment strategies for gastric cancer have developed. Immune check point inhibitors (ICIs) have been detected as a new standard treatment in Gastric cancer, which helped to improve the prognosis of patients with gastric cancer. Attempts to combine immunotherapy have become one of the research focuses. In this article, application of immunotherapy in neoadjuvant therapy and translational treatment of gastric cnacer are reviewed. Which is expected to be a reference for comprehensive treatment plan of accurate treatment methods for gastric cancer patients. In order to provide experiences and reference to develop individualized treatment of gastric cancer in clinical practice.

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The efficacy and safety of short-course radiotherapy followed by sequential chemotherapy and Cadonilimab for locally advanced rectal cancer: a protocol of a phase II study

Xu,

Feng,

Zhang

et al. 2024

BMC Cancer

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Background For patients with locally advanced rectal cancer (LARC), total neoadjuvant therapy (TNT), namely, intensifying preoperative treatment through the integration of radiotherapy and systemic chemotherapy before surgery, was commonly recommended as the standard treatment. However, the risk of distant metastasis at 3 years remained higher than 20%, and the complete response (CR) rate was less than 30%. Several clinical trials had suggested a higher complete response rate when combining single-agent immunotherapy with short-course radiotherapy (SCRT). The CheckMate 142 study had shown encouraging outcomes of dual immunotherapy and seemingly comparable toxicity for CRC compared with single-agent immunotherapy in historical results. Therefore, dual immunotherapy might be more feasible in conjunction with the TNT paradigm of SCRT. We performed a phase II study to investigate whether the addition of a dual immune checkpoint inhibitor bispecific antibody, Cadonilimab, to SCRT combined with chemotherapy might further increase the clinical benefit and prognosis for LARC patients. Methods This single-arm, multicenter, prospective, phase II study included patients with pathologically confirmed cT3-T4N0 or cT2-4N + rectal adenocarcinoma with an ECOG performance score of 0 or 1. Bispecific antibody immunotherapy was added to SCRT combined with chemotherapy. Patients enrolled would be treated with SCRT (25 Gy in five fractions over 1 week) for the pelvic cavity, followed by 4 cycles of CAPOX or 6 cycles of mFOLFOX and Cadonilimab. The primary endpoint was the CR rate, which was the ratio of the pathological CR rate plus the clinical CR rate. The secondary endpoints included local–regional control, distant metastasis, disease-free survival, overall survival, toxicity profile, quality of life and functional outcome of the rectum. To detect an increase in the complete remission rate from 21.8% to 40% with 80% power, 50 patients were needed. Discussion This study would provide evidence on the efficacy and safety of SCRT plus bispecific antibody immunotherapy combined with chemotherapy as neoadjuvant therapy for patients with LARC, which might be used as a candidate potential therapy in the future. Trial registration This phase II trial was prospectively registered at ClinicalTrials.gov, under the identifier NCT05794750.

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A phase Ib/II study of AK104, a PD-1/CTLA-4 bispecific antibody, combined with mXELOX as first-line therapy for advanced gastric or gastroesophageal junction (GEJ) adenocarcinoma

Cited by 3 publications

References 0 publications

Cytotoxic T‐lymphocyte‐associated protein 4 in gastric cancer: Prognosis and association with PD‐L1 expression

Cytotoxic T‐lymphocyte‐associated protein 4 in gastric cancer: Prognosis and association with PD‐L1 expression

Current status of immunotherapy in gastric cancer

The efficacy and safety of short-course radiotherapy followed by sequential chemotherapy and Cadonilimab for locally advanced rectal cancer: a protocol of a phase II study

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