CStone Pharmaceuticals announced groundbreaking clinical data for CS2009, marking the first-ever disclosure of clinical results for a PD-1/VEGF/CTLA-4 trispecific antibody at the 2025 European Society for Medical Oncology (ESMO) Annual Congress in Berlin. The Phase I dose-escalation study demonstrated promising safety and efficacy signals across multiple advanced solid tumor types.
Phase I Study Design and Patient Population
The CS2009-101 multi-regional Phase I study is currently ongoing in Australia and China, evaluating safety, tolerability, pharmacokinetics, pharmacodynamics, and antitumor activity in patients with advanced solid tumors. As of the data cutoff date, 72 patients were treated across six dose levels ranging from 1-45 mg/kg, with 72.2% remaining on treatment.
The study enrolled a heavily pretreated population, with over 51% of patients having received prior immuno-oncology therapies. The median follow-up was 1.9 months (range 0.1-6.7 months) at the time of data cutoff.
Safety Profile Shows Favorable Tolerability
CS2009 demonstrated a favorable safety profile throughout dose escalation. No dose-limiting toxicities were reported, and the maximum tolerated dose was not reached. Notably, no Grade 4 or 5 treatment-related adverse events were observed.
The incidence of Grade ≥3 treatment-related adverse events was 13.9%, while immune-related adverse events occurred in 4.2% of patients and VEGF-related treatment-related adverse events in 2.8%. Only one treatment-emergent adverse event led to permanent drug discontinuation, occurring at the 20 mg/kg dose level with a 1.4% incidence.
Encouraging Antitumor Activity Across Multiple Tumor Types
Despite the limited follow-up duration, CS2009 demonstrated encouraging anti-tumor activity across all dose levels with a dose-dependent uptrend. Among 49 evaluable patients who underwent at least one post-baseline tumor assessment, the overall response rate was 12.2% and the disease control rate was 71.4%.
With additional follow-up beyond the poster data cutoff, the overall response rate improved to 14.3%. Higher response rates of 25.0% were observed at the tentative recommended Phase 2 dose of 30 mg/kg and higher doses.
Tumor-Specific Efficacy Signals
CS2009 showed promising efficacy signals across multiple tumor types within the short follow-up period:
-
Non-Small Cell Lung Cancer (NSCLC): Overall response rate of 11.8% and disease control rate of 82.4%. Post-ESMO updates showed stable disease-to-partial response conversion, elevating the response rate to 17.6%. In the AGA-negative subgroup, the response rate reached 25%.
-
Ovarian Cancer: Overall response rate of 16.7% with a disease control rate of 66.7%.
-
Triple-Negative Breast Cancer: Overall response rate of 25.0% and disease control rate of 75.0%.
-
Non-Clear Cell Renal Cell Carcinoma: Overall response rate of 33.3% with a disease control rate of 100.0%.
-
Soft Tissue Sarcoma: Overall response rate of 11.1% and disease control rate of 66.7%.
Pharmacokinetic and Pharmacodynamic Properties
CS2009 exhibited linear pharmacokinetics with a half-life of 6-8 days, supporting every-three-week dosing with no significant accumulation observed at cycle 3. The pharmacodynamic profile demonstrated saturated receptor occupancy and robust T-cell activation and proliferation, confirming effective PD-1/CTLA-4 blockade and deep, sustained VEGFA neutralization.
Receptor occupancy of PD-1/CTLA-4 on peripheral T cells reached saturation throughout the dosing interval at doses ≥20 mg/kg. On cycle 1 day 8, CS2009 induced notable, dose-dependent upregulation of Ki67 and ICOS expression on both CD4+ and CD8+ T cells, demonstrating effective PD-1 and CTLA-4 inhibition.
Serum-free VEGFA was reduced deeply and rapidly across all dose levels, with the effect sustained throughout dose intervals.
Future Development Plans
CStone has initiated Phase II dose expansion studies in first-line patients with selected tumor types for dose optimization and to generate data supporting registration trials in first-line NSCLC and other tumors as monotherapy or in combination therapies.
The company also presented the Phase Ib study design for CS5001, a ROR1-targeted antibody-drug conjugate, with patient enrollment commencing in December 2024 and currently advancing at 30 sites across Australia, the United States, and China.
