On March 4, 2025 CStone Pharmaceuticals (stock code: 2616.HK), an innovation-driven biopharmaceutical company focused on the research and development of anti-cancer drugs, reported that the first patient has been successfully dosed in a global, multi-center Phase I clinical trial of CS2009, its independently developed PD-1/VEGF/CTLA-4 trispecific antibody, with no infusion reactions or other adverse events (Press release, CStone Pharmaceauticals, MAR 4, 2025, View Source [SID1234656221]).
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The trial will deeply evaluate the clinical application value of CS2009 in a variety of advanced solid tumors, including non-small cell lung cancer, liver cancer, gastric cancer, endometrial cancer, ovarian cancer, renal cell carcinoma and cervical cancer, thereby promoting the innovation and development of tumor immunotherapy.
CS2009 is a novel trispecific antibody independently developed by CStone Pharmaceuticals from the molecular design perspective. It targets three clinically validated targets— PD-1, VEGFA, and CTLA-4 —to achieve multi-dimensional anti-tumor effects through synergistic action. Specifically, PD-1 blockade reverses T cell exhaustion, CTLA-4 blockade promotes T cell activation and proliferation, and VEGFA blockade inhibits tumor angiogenesis, thereby improving the tumor microenvironment (TME). Within the TME, the dual PD-1 and CTLA-4 blockade is significantly enhanced by cross-linking with VEGFA. Furthermore, CS2009 preferentially binds to tumor-infiltrating T cells that are both PD-1 and CTLA-4 positive, while minimizing interference with the CTLA-4 regulatory pathway in peripheral T cells. This innovative molecular design is expected to enhance efficacy while minimizing systemic toxicity.
Preclinical studies have shown that CS2009’s anti-tumor activity is superior to that of potential competitors. Furthermore, by combining CTLA-4 inhibition with PD-1 and VEGFA targeting, CS2009 is expected to further enhance the efficacy of PD-L1-low or PD-L1-negative patients who have poor responses to PD-(L)1 therapy . This potential makes CS2009 a first-in-class/best-in-class next-generation immuno-oncology backbone product, potentially replacing existing PD-(L)1-based therapies .
Dr. Jianxin Yang, CEO, President of R&D, and Executive Director of CStone Pharmaceuticals, said: "The successful initiation of the first-in-human study of CS2009 marks the official entry of this innovative therapy into the clinical validation phase. Existing preclinical data have demonstrated its potential across a broad range of indications. In vitro data demonstrate that CS2009 specifically activates tumor-infiltrating T cells and effectively synergizes with VEGF antagonism . In immunocompetent mouse models, CS2009 demonstrated superior tumor killing efficacy compared to both PD-1/CTLA-4 and PD-1/VEGF dual antibodies . Toxicology studies have demonstrated that the safe dose level of CS2009 is significantly higher than that of PD-1/CTLA-4 dual antibodies and comparable to that of PD-1/VEGF dual antibodies . Based on this, we are confident in the clinical potential of CS2009 and look forward to the early release of clinical data further demonstrating its excellent safety profile and anti-tumor activity, which will open a new chapter for the next generation of cancer immunotherapy."
Dr. Qingmei Shi, Chief Medical Officer of CStone Pharmaceuticals, said , "We are delighted to see CS2009 successfully achieve the first patient dose milestone. As an innovative trispecific antibody, CS2009 not only balances efficacy and safety, but also has the potential to overcome the treatment bottleneck for patients with low or negative PD-L1 expression . We look forward to rapid and positive progress in this study, providing better treatment options for solid tumor patients worldwide. We are also very grateful to the CStone clinical team for completing the entire process from Australian clinical trial application submission to first patient dosing in just over two months, despite multiple domestic and international holidays. This fully demonstrates CStone’s exceptional clinical development efficiency and unwavering commitment to serving patients."
Currently, CS2009 is first conducting a multi-center Phase I clinical trial in Australia, and will gradually expand to China and the United States in the future.
About CS2009 (PD-1/VEGF/CTLA-4 trispecific antibody)
CS2009 is a trispecific molecule targeting PD-1, VEGFA, and CTLA-4. As a trispecific antibody targeting large tumor types, it holds first-in-class/best-in-class potential. CS2009 boasts a differentiated molecular design, combining three clinically validated targets to reactivate near-exhausted tumor-infiltrating T cells and demonstrates VEGF neutralization activity comparable to that of existing anti-VEGF antibodies. It covers a wide range of disease indications, including non-small cell lung cancer, liver cancer, gastric cancer, endometrial cancer, ovarian cancer, renal cell carcinoma, and cervical cancer.
In November 2024, CStone Pharmaceuticals presented preclinical data for CS2009 at the 39th Annual Meeting of the Society for Immunotherapy of Cancer (SITC) (Free SITC Whitepaper). These data demonstrated that CS2009 exhibited significantly superior anti-tumor activity compared to potential competing products, including dual PD-1/CTLA-4 antibodies, dual PD-1/VEGF antibodies, and anti-PD-1/anti-CTLA-4 combination therapies.