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Tislelizumab in previously treated, locally advanced unresectable/metastatic microsatellite instability-high/mismatch
Jian Li1, Ye Xu2, Aimin Zang3
1State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers, Beijing Key Laboratory of Carcinogenesis and Translational Research, Department of Gastrointestinal Oncology, Peking University Cancer Hospital & Institute, Beijing 100142, China.
Objective:
The open-label, phase II RATIONALE-209 study evaluated tislelizumab (anti-programmed cell death protein 1 antibody) as a tissue-agnostic monotherapy for microsatellite instability-high (MSI-H)/mismatch repair-deficient (dMMR) tumors.
Methods:
Adults with previously treated, locally advanced unresectable or metastatic MSI-H/dMMR solid tumors were enrolled. Patients received tislelizumab 200 mg intravenously every 3 weeks. Objective response rate (ORR; primary endpoint), duration of response (DoR), and progression-free survival (PFS) were assessed by independent review committee (Response Evaluation Criteria in Solid Tumors v1.1).
Results:
Eighty patients were enrolled and treated; 75 (93.8%) patients had measurable disease at baseline. Most had metastatic disease and received at least one prior therapy for advanced/metastatic disease (n=79; 98.8%). At primary analysis (data cutoff July 8, 2021; median follow-up 15.2 months), overall ORR [46.7%; 95% confidence interval (95% CI), 35.1-58.6; one-sided P<0.0001] and ORR across tumor-specific subgroups [colorectal (n=46): 39.1% (95% CI, 25.1-54.6); gastric/gastroesophageal junction (n=9): 55.6% (95% CI, 21.2-86.3); others (n=20): 60.0% (95% CI, 36.1-80.9)] were significantly greater with tislelizumab vs. a prespecified historical control ORR of 10%; five (6.7%) patients had complete responses. Median DoR, PFS, and overall survival were not reached with long-term follow-up (data cutoff December 5, 2022; median follow-up 28.9 months). Tislelizumab was well tolerated with no unexpected safety signals. Treatment-related adverse events (TRAEs) of grade ≥3 occurred in 53.8% of patients; 7.5% of patients discontinued treatment due to TRAEs.
Conclusions:
Tislelizumab demonstrated a significant ORR improvement in patients with previously treated, locally advanced unresectable or metastatic MSI-H/dMMR tumors and was generally well tolerated.
Insights
Tislelizumab, an anti-PD-1 antibody, significantly improved objective response rates in patients with previously treated MSI-H/dMMR solid tumors. The immunotherapy was well-tolerated, showing promising results in this difficult-to-treat population.
Area of Science:
- Oncology
- Immunotherapy
- Solid Tumors
Background:
- Microsatellite instability-high (MSI-H)/mismatch repair-deficient (dMMR) solid tumors represent a distinct molecular subtype with varying responses to treatment.
- Tislelizumab is an anti-programmed cell death protein 1 (PD-1) antibody investigated for its therapeutic potential.
Purpose of the Study:
- To evaluate tislelizumab as a tissue-agnostic monotherapy in adult patients with previously treated, locally advanced unresectable or metastatic MSI-H/dMMR solid tumors.
- To assess the objective response rate (ORR) as the primary endpoint, along with duration of response (DoR) and progression-free survival (PFS).
Main Methods:
- An open-label, phase II study (RATIONALE-209) enrolled patients with MSI-H/dMMR solid tumors.
- Patients received tislelizumab 200 mg intravenously every 3 weeks.
- Outcomes were assessed by an independent review committee using Response Evaluation Criteria in Solid Tumors v1.1.
Main Results:
- The overall ORR was 46.7%, significantly exceeding the historical control of 10% (P<0.0001).
- Responses were observed across various tumor subgroups, including colorectal, gastric, and gastroesophageal junction cancers.
- Median DoR, PFS, and overall survival were not reached at long-term follow-up; tislelizumab was well-tolerated with manageable adverse events.
Conclusions:
- Tislelizumab demonstrated a significant improvement in ORR for patients with previously treated MSI-H/dMMR solid tumors.
- The anti-PD-1 antibody was generally well-tolerated, supporting its potential as a treatment option for this patient population.
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